AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

Drug design

 

Drug design

Drug design, sometimes referred to as rational drug design or more simply rational design, is the inventive process of finding new medications based on the knowledge of a biological target.[1] The drug is most commonly an organic small molecule that activates or inhibits the function of a biomolecule such as a protein, which in turn results in a therapeutic benefit to the patient. In the most basic sense, drug design involves the design of small molecules that are complementary in shape and charge to the biomolecular target with which they interact and therefore will bind to it. Drug design frequently but not necessarily relies on computer modeling techniques.[2] This type of modeling is often referred to as computer-aided drug design. Finally, drug design that relies on the knowledge of the three-dimensional structure of the biomolecular target is known as structure-based drug design.

The phrase “drug design” is to some extent a misnomer. What is really meant by drug design is ligand design (i.e., design of a small molecule that will bind tightly to its target).[3] Although modeling techniques for prediction of binding affinity are reasonably successful, there are many other properties, such as bioavailability, metabolic half-life, lack of side effects, etc., that first must be optimized before a ligand can become a safe and efficacious drug. These other characteristics are often difficult to optimize using rational drug design techniques.

Background

Typically a drug target is a key molecule involved in a particular metabolic or signaling pathway that is specific to a disease condition or pathology or to the infectivity or survival of a microbial pathogen. Some approaches attempt to inhibit the functioning of the pathway in the diseased state by causing a key molecule to stop functioning. Drugs may be designed that bind to the active region and inhibit this key molecule. Another approach may be to enhance the normal pathway by promoting specific molecules in the normal pathways that may have been affected in the diseased state. In addition, these drugs should also be designed so as not to affect any other important “off-target” molecules or antitargets that may be similar in appearance to the target molecule, since drug interactions with off-target molecules may lead to undesirable side effects. Sequence homology is often used to identify such risks.

Most commonly, drugs are organic small molecules produced through chemical synthesis, but biopolymer-based drugs (also known as biologics) produced through biological processes are becoming increasingly more common. In addition, mRNA-based gene silencing technologies may have therapeutic applications.

Types

Flow charts of two strategies of structure-based drug design

There are two major types of drug design. The first is referred to as ligand-based drug design and the second, structure-based drug design.

Ligand-based

Ligand-based drug design (or indirect drug design) relies on knowledge of other molecules that bind to the biological target of interest. These other molecules may be used to derive a pharmacophore model that defines the minimum necessary structural characteristics a molecule must possess in order to bind to the target.[4] In other words, a model of the biological target may be built based on the knowledge of what binds to it, and this model in turn may be used to design new molecular entities that interact with the target. Alternatively, a quantitative structure-activity relationship (QSAR), in which a correlation between calculated properties of molecules and their experimentally determined biological activity, may be derived. These QSAR relationships in turn may be used to predict the activity of new analogs.

Structure-based

Structure-based drug design (or direct drug design) relies on knowledge of the three dimensional structure of the biological target obtained through methods such as x-ray crystallography or NMR spectroscopy.[5] If an experimental structure of a target is not available, it may be possible to create a homology model of the target based on the experimental structure of a related protein. Using the structure of the biological target, candidate drugs that are predicted to bind with high affinity and selectivity to the target may be designed using interactive graphics and the intuition of a medicinal chemist. Alternatively various automated computational procedures may be used to suggest new drug candidates.

As experimental methods such as X-ray crystallography and NMR develop, the amount of information concerning 3D structures of biomolecular targets has increased dramatically. In parallel, information about the structural dynamics and electronic properties about ligands has also increased. This has encouraged the rapid development of the structure-based drug design. Current methods for structure-based drug design can be divided roughly into two categories. The first category is about “finding” ligands for a given receptor, which is usually referred as database searching. In this case, a large number of potential ligand molecules are screened to find those fitting the binding pocket of the receptor. This method is usually referred as ligand-based drug design. The key advantage of database searching is that it saves synthetic effort to obtain new lead compounds. Another category of structure-based drug design methods is about “building” ligands, which is usually referred as receptor-based drug design. In this case, ligand molecules are built up within the constraints of the binding pocket by assembling small pieces in a stepwise manner. These pieces can be either individual atoms or molecular fragments. The key advantage of such a method is that novel structures, not contained in any database, can be suggested.[6][7][8]

Active site identification

Active site identification is the first step in this program. It analyzes the protein to find the binding pocket, derives key interaction sites within the binding pocket, and then prepares the necessary data for Ligand fragment link. The basic inputs for this step are the 3D structure of the protein and a pre-docked ligand in PDB format, as well as their atomic properties. Both ligand and protein atoms need to be classified and their atomic properties should be defined, basically, into four atomic types:

  • hydrophobic atom: All carbons in hydrocarbon chains or in aromatic groups.
  • H-bond donor: Oxygen and nitrogen atoms bonded to hydrogen atom(s).
  • H-bond acceptor: Oxygen and sp2 or sp hybridized nitrogen atoms with lone electron pair(s).
  • Polar atom: Oxygen and nitrogen atoms that are neither H-bond donor nor H-bond acceptor, sulfur, phosphorus, halogen, metal, and carbon atoms bonded to hetero-atom(s).

The space inside the ligand binding region would be studied with virtual probe atoms of the four types above so the chemical environment of all spots in the ligand binding region can be known. Hence we are clear what kind of chemical fragments can be put into their corresponding spots in the ligand binding region of the receptor.

Ligand fragment link

Flow chart for structure-based drug design

When we want to plant “seeds” into different regions defined by the previous section, we need a fragments database to choose fragments from. The term “fragment” is used here to describe the building blocks used in the construction process. The rationale of this algorithm lies in the fact that organic structures can be decomposed into basic chemical fragments. Although the diversity of organic structures is infinite, the number of basic fragments is rather limited.

Before the first fragment, i.e. the seed, is put into the binding pocket, and other fragments can be added one by one, it is useful to identify potential problems. First, the possibility for the fragment combinations is huge. A small perturbation of the previous fragment conformation would cause great difference in the following construction process. At the same time, in order to find the lowest binding energy on the Potential energy surface (PES) between planted fragments and receptor pocket, the scoring function calculation would be done for every step of conformation change of the fragments derived from every type of possible fragments combination. Since this requires a large amount of computation, one may think using other possible strategies to let the program works more efficiently. When a ligand is inserted into the pocket site of a receptor, conformation favor for these groups on the ligand that can bind tightly with receptor should be taken priority. Therefore it allows us to put several seeds at the same time into the regions that have significant interactions with the seeds and adjust their favorite conformation first, and then connect those seeds into a continuous ligand in a manner that make the rest part of the ligand having the lowest energy. The conformations of the pre-placed seeds ensuring the binding affinity decide the manner that ligand would be grown. This strategy reduces calculation burden for the fragment construction efficiently. On the other hand, it reduces the possibility of the combination of fragments, which reduces the number of possible ligands that can be derived from the program. These two strategies above are well used in most structure-based drug design programs. They are described as “Grow” and “Link”. The two strategies are always combined in order to make the construction result more reliable.[6][7][9]

Scoring method

Structure-based drug design attempts to use the structure of proteins as a basis for designing new ligands by applying accepted principles of molecular recognition. The basic assumption underlying structure-based drug design is that a good ligand molecule should bind tightly to its target. Thus, one of the most important principles for designing or obtaining potential new ligands is to predict the binding affinity of a certain ligand to its target and use it as a criterion for selection.

One early method was developed by Böhm[10] to develop a general-purposed empirical scoring function in order to describe the binding energy. The following “Master Equation” was derived:

\begin{array}{lll}\Delta G_{\text{bind}} = -RT \ln K_{\text{d}}\\[1.3ex]<br /><br /><br /><br /><br /><br /><br /><br /><br /><br />
K_{\text{d}} = \dfrac{[\text{Receptor}][\text{Acceptor}]}{[\text{Complex}]}\\[1.3ex]</p><br /><br /><br /><br /><br /><br /><br /><br /><br />
<p>\Delta G_{\text{bind}} = \Delta G_{\text{desolvation}} + \Delta G_{\text{motion}} + \Delta G_{\text{configuration}} + \Delta G_{\text{interaction}}\end{array}

where:

  • desolvation – enthalpic penalty for removing the ligand from solvent
  • motion – entropic penalty for reducing the degrees of freedom when a ligand binds to its receptor
  • configuration – conformational strain energy required to put the ligand in its “active” conformation
  • interaction – enthalpic gain for “resolvating” the ligand with its receptor

The basic idea is that the overall binding free energy can be decomposed into independent components that are known to be important for the binding process. Each component reflects a certain kind of free energy alteration during the binding process between a ligand and its target receptor. The Master Equation is the linear combination of these components. According to Gibbs free energy equation, the relation between dissociation equilibrium constant, Kd, and the components of free energy was built.

Various computational methods are used to estimate each of the components of the master equation. For example, the change in polar surface area upon ligand binding can be used to estimate the desolvation energy. The number of rotatable bonds frozen upon ligand binding is proportional to the motion term. The configurational or strain energy can be estimated using molecular mechanics calculations. Finally the interaction energy can be estimated using methods such as the change in non polar surface, statistically derived potentials of mean force, the number of hydrogen bonds formed, etc. In practice, the components of the master equation are fit to experimental data using multiple linear regression. This can be done with a diverse training set including many types of ligands and receptors to produce a less accurate but more general “global” model or a more restricted set of ligands and receptors to produce a more accurate but less general “local” model.[11][12][13]

Rational drug discovery

In contrast to traditional methods of drug discovery, which rely on trial-and-error testing of chemical substances on cultured cells or animals, and matching the apparent effects to treatments, rational drug design begins with a hypothesis that modulation of a specific biological target may have therapeutic value. In order for a biomolecule to be selected as a drug target, two essential pieces of information are required. The first is evidence that modulation of the target will have therapeutic value. This knowledge may come from, for example, disease linkage studies that show an association between mutations in the biological target and certain disease states. The second is that the target is “drugable”. This means that it is capable of binding to a small molecule and that its activity can be modulated by the small molecule.

Once a suitable target has been identified, the target is normally cloned and expressed. The expressed target is then used to establish a screening assay. In addition, the three-dimensional structure of the target may be determined.

The search for small molecules that bind to the target is begun by screening libraries of potential drug compounds. This may be done by using the screening assay (a “wet screen”). In addition, if the structure of the target is available, a virtual screen may be performed of candidate drugs. Ideally the candidate drug compounds should be “drug-like”, that is they should possess properties that are predicted to lead to oral bioavailability, adequate chemical and metabolic stability, and minimal toxic effects. Several methods are available to estimate druglikeness such as Lipinski’s Rule of Five and a range of scoring methods such as Lipophilic efficiency. Several methods for predicting drug metabolism have been proposed in the scientific literature, and a recent example is SPORCalc.[14] Due to the complexity of the drug design process, two terms of interest are still serendipity and bounded rationality. Those challenges are caused by the large chemical space describing potential new drugs without side-effects.

Computer-aided drug design

Computer-aided drug design uses computational chemistry to discover, enhance, or study drugs and related biologically active molecules. The most fundamental goal is to predict whether a given molecule will bind to a target and if so how strongly. Molecular mechanics or molecular dynamics are most often used to predict the conformation of the small molecule and to model conformational changes in the biological target that may occur when the small molecule binds to it. Semi-empirical, ab initio quantum chemistry methods, or density functional theory are often used to provide optimized parameters for the molecular mechanics calculations and also provide an estimate of the electronic properties (electrostatic potential, polarizability, etc.) of the drug candidate that will influence binding affinity.

Molecular mechanics methods may also be used to provide semi-quantitative prediction of the binding affinity. Also, knowledge-based scoring function may be used to provide binding affinity estimates. These methods use linear regression, machine learning, neural nets or other statistical techniques to derive predictive binding affinity equations by fitting experimental affinities to computationally derived interaction energies between the small molecule and the target.[15][16]

Ideally the computational method should be able to predict affinity before a compound is synthesized and hence in theory only one compound needs to be synthesized. The reality however is that present computational methods are imperfect and provide at best only qualitatively accurate estimates of affinity. Therefore in practice it still takes several iterations of design, synthesis, and testing before an optimal molecule is discovered. On the other hand, computational methods have accelerated discovery by reducing the number of iterations required and in addition have often provided more novel small molecule structures.

Drug design with the help of computers may be used at any of the following stages of drug discovery:

  1. hit identification using virtual screening (structure- or ligand-based design)
  2. hit-to-lead optimization of affinity and selectivity (structure-based design, QSAR, etc.)
  3. lead optimization optimization of other pharmaceutical properties while maintaining affinity
Flowchart of a common Clustering Analysis for Structure-Based Drug Design

Flowchart of a Usual Clustering Analysis for Structure-Based Drug Design

In order to overcome the insufficient prediction of binding affinity calculated by recent scoring functions, the protein-ligand interaction and compound 3D structure information are used to analysis. For structure-based drug design, several post-screening analysis focusing on protein-ligand interaction has been developed for improving enrichment and effectively mining potential candidates:

  • Consensus scoring[17][18]
    • Selecting candidates by voting of multiple scoring functions
    • May lose the relationship between protein-ligand structural information and scoring criterion
  • Geometric analysis
    • Comparing protein-ligand interactions by visually inspecting individual structures
    • Becoming intractable when the number of complexes to be analyzed increasing
  • Cluster analysis[19][20]
    • Represent and cluster candidates according to protein-ligand 3D information
    • Needs meaningful representation of protein-ligand interactions.

Examples

A particular example of rational drug design involves the use of three-dimensional information about biomolecules obtained from such techniques as X-ray crystallography and NMR spectroscopy. Computer-aided drug design in particular becomes much more tractable when there’s a high-resolution structure of a target protein bound to a potent ligand. This approach to drug discovery is sometimes referred to as structure-based drug design. The first unequivocal example of the application of structure-based drug design leading to an approved drug is the carbonic anhydrase inhibitor dorzolamide, which was approved in 1995.[21][22]

Another important case study in rational drug design is imatinib, a tyrosine kinase inhibitor designed specifically for the bcr-abl fusion protein that is characteristic for Philadelphia chromosome-positive leukemias (chronic myelogenous leukemia and occasionally acute lymphocytic leukemia). Imatinib is substantially different from previous drugs for cancer, as most agents of chemotherapy simply target rapidly dividing cells, not differentiating between cancer cells and other tissues.

References
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  2. Cohen, N. Claude (1996). Guidebook on Molecular Modeling in Drug Design. Boston: Academic Press. ISBN 0-12-178245-X.
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  23. http://autodock.scripps.edu/news/autodocks-role-in-developing-the-first-clinically-approved-hiv-integrase-inhibitor

External links

Zinc Database, ChEMBL, Chemspider, Bingo, JChem for Excel, ChemDiff, Protein DataBank (PDB), Binding MOAD (Mother Of All Database), Ligand Protein DataBase (LPDB), TTD, STITCH, SMPDB, …

Chemical databases

  • Zinc Database. Curated collection of commercially available chemical compounds, with 3D coordinates, provided by the Shoichet Laboratory in the Department of Pharmaceutical Chemistry at the University of California, San Francisco (UCSF).
  • ChEMBL. Curated database of small molecules. Includes interactions and functional effects of small molecules binding to their macromolecular targets, and series of drug discovery databases.
  • Chemspider. Collection of chemical compunds maintained by the Royal Society of Chemistry. Includes the conversion of chemical names to chemical structures, the generation of SMILES and InChI strings as well as the prediction of many physicochemical parameters.
  • CoCoCo. Free suite of multiconformational molecular databases for High-Throughput Virtual Screening. It has single and multi conformer databases prepared for HTVS in different formats like Phase, Catalyst, Unity and SDF. Provided by the Department of Pharmaceutical Sciences of the University of Modena and Reggio Emilia.
  • DrugBank. Bioinformatics and cheminformatics resource combining detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. Allows searching for similar compounds.
  • Mcule database. Commercial database of commercially available small molecules. Allows filtering by chemical supplier data (stock availability, price, delivery time, chemical suppliers, catalogs, minimum purity, etc.) and export the whole Mcule database including supplier and procurement related properties. Reduced prices for academic. Provided by Mcule.
  • PubChem. Database of chemical compounds maintained by the National Center for Biotechnology Information (NCBI), along with bioassays results. Allows similar compounds search (2D and 3D).
  • PubChem Mobile. Free application to search PubChem databases using chemical names, synonyms, and keywords. For Android.
  • WOMBAT. (World of Molecular Bioactivity). Database of 331,872 entries (268,246 unique SMILES), representing 1,966 unique targets, with bioactivity annotations. Compiled by Sunset Molecular Discovery LLC.
  • Approved Drugs. The Approved Drugs app contains over a thousand chemical structures and names of small molecule drugs approved by the US Food & Drug Administration (FDA). Structures and names can be browsed in a list, searched by name, filtered by structural features, and ranked by similarity to a user-drawn structure. The detail view allows viewing of a 3D conformation as well as tautomers. Structures can be exported in a variety of ways, e.g. email, twitter, clipboard. For iPad and iPhone. Developed by Molecular Materials Informatics, Inc.
  • e-Drug3D. Database mirroring the current content of the U.S. pharmacopeia of small drugs. Contains 1533 molecular structures with a molecular weight < 2000 (last update: February 2012). Provides SD files (single conformer, tautomers or multiple conformers). Maintained by the Institut de Pharmacologie Moléculaire et Cellulaire, France.
  • ChemDB/ChemicalSearch. Find chemicals by various search criteria.
  • Structural Database (CSD). Repository for small molecule crystal structures in CIF format. The CSD is compiled and maintained by the Cambridge Crystallographic Data Centre
  • SPRESIweb. Integrated database containing over 8.7 million molecules, 4.1 million reactions, 658,000 references and 164,000 patents covering the years 1974 – 2009. Developed by InfoChem.
  • MMsINC. Database of non-redundant, annotated and biomedically relevant chemical structures. Includes the analysis of chemical properties, such as ionization and tautomerization processes, and the in silico prediction of 24 important molecular properties in the biochemical profile of each structure. MMsINC supports various types of queries, including substructure queries and the novel ‘molecular scissoring’ query. MMsINC is interfaced with other primary data collectors, such as PubChem, Protein Data Bank (PDB), the Food and Drug Administration database of approved drugs and ZINC. provided by the CRS4 – Bioinformatics Laboratory, Parco Sardegna Ricerche, Italy.
  • SPRESImobile. iPod, iPhone and iPad application providing direct access to ChemReact, a subset of the SPRESI structure and reaction database, which contains more than 400,000 unique reaction types and the related references. Developed by InfoChem.
  • MORE. (MObile REagents). Mobile app, for iphone, ipad and android, which gives access to over 9 million molecules and 16 million chemical product variations offered by 56 different suppliers. Can search reagents by name, formula or by drawing a chemical structure. It is possible to limit the search to specific suppliers, bookmark the search results, and export small sdfiles. Allows converting a picture of a chemical structure taken from the iPhone camera into a structurally searchable molecule using OSRA (Optical Structure Recognition Application).
  • KKB. (Kinase Knowledgebase). Database of kinase structure-activity and chemical synthesis data. Developed and maintained by Eidogen-Sertanty, Inc.
  • iKinase Universal. iPad/iPhone application providing sample structure activity data from Eidogen-Sertanty’s Kinase Knowledgebase (KKB). Exists in a Pro version (iKinasePro).
  • DUD.E. (Database of Useful Decoys: Enhanced). DUD-E is designed to help test docking algorithms by providing challenging decoys. It contains a total 22,886 active compounds and their affinities against 102 targets, an average of 224 ligands per target. Also includes 50 decoys for each active, having similar physico-chemical properties but dissimilar 2-D topology. DUD-E is provided freely by the Shoichet Laboratory in the Department of Pharmaceutical Chemistry at the University of California, San Francisco (UCSF).
  • DUD. (Directory of Useful Decoys). DUD is designed to help test docking algorithms by providing challenging decoys. It contains a total of 2,950 active compounds against a total of 40 targets. For each active, 36 “decoys” with similar physical properties (e.g. molecular weight, calculated LogP) but dissimilar topology. DUD is provided freely by the Shoichet Laboratory in the Department of Pharmaceutical Chemistry at the University of California, San Francisco (UCSF).
  • MUV. Maximum Unbiased Validation Datasets for Virtual Screening, with non-clumpy, spatially random topology. Provided by Carolo-Wilhelmina University.
  • GLL. (GPCR Ligand Library). Database of 25145 ligands for 147 GPCRs. Associated with the GDD (GPCR Decoy Database). Provided by the Claudio N. Cavasotto Lab. of the Instituto de Biomedicina de Buenos Aires – Max Planck Society Partner (IBioBA-MPSP).
  • GDD. (GPCR Decoy Database). For each ligand in GLL, 39 decoys were drawn from ZINC ensuring physical similarity of six properties (molecular weight, formal charge, hydrogen bond donors and acceptors, rotatable bonds and logP), but structural dissimilarity. Provided by the Claudio N. Cavasotto Lab. of the Instituto de Biomedicina de Buenos Aires – Max Planck Society Partner (IBioBA-MPSP).
  • VDS. Virtual Decoy Sets for Molecular Docking Benchmarks. Similar to DUD but ignoring synthetic feasibility. Expected to be less biased with respect to physical similarity.
  • DNP. (Dictionary of Natural Products). Comprehensive and fully-edited database on natural products, arising from the Dictionary of Organic Compounds (DOC).The compilation of DNP is undertaken by a team of academics and freelancers who work closely with the in-house editorial staff at Chapman & Hall. Each contributor specialises in a particular natural product class (e.g. alkaloids) and reorganises and classifies the data in the light of new research so as to present it in the most consistent and logical manner possible.
  • ChemIDPlus. Database of compounds and structures by US National Library of Medicine
  • ChemBank. Public, web-based informatics environment created by the Broad Institute’s Chemical Biology Program. Includes freely available data derived from small molecules and small-molecule screens, and resources for studying the data.
  • eMolecules. Database of unique molecules from commercial suppliers
  • GLIDA. GPCR-Ligand Database. Provides information on both GPCRs and their known ligands. Enterable either by GPCR search or ligand search. Maintained by the PharmacoInformatics Laboratory, Kyoto University.
  • TCM. Free small molecular database on traditional Chinese medicine for virtual screening.
  • Comparative Toxicogenomics Database (CTD). Database of manually curated data describing cross-species chemical-gene/protein interactions and chemical and gene disease relationships to illuminate molecular mechanisms underlying variable susceptibility and environmentally influenced diseases.
  • SuperDrug Database. Database of about 3000 molecules, with about 40 conformers each. Allows 2D similarity search and 3D superposition.
  • Ligand Expo. Formerly Ligand Depot. Provides chemical and structural information about small molecules within the structure entries of the Protein Data Bank.
  • Glide Ligand Decoys Set. Collection created by selecting 1000 ligands from a one million compound library that were chosen to exhibit “drug-like” properties. Used in Glide enrichment studies. Provided by Schrödinger.
  • Glide Fragment Library. Set of 441 unique small fragments (1-7 ionization/tautomer variants; 6-37 atoms; MW range 32-226) derived from molecules in the medicinal chemistry literature. The set includes a total of 667 fragments with accessible low energy ionization and tautomeric states and metal and state penalties for each compound from Epik. These can be used for fragment docking, core hopping, lead optimization, de novo design, etc. Provided by Schrödinger.
  • Virtual library Repository. Libraries of 30,184 (redundant) and 4,544 small-molecule fragments, all less than 150 daltons in weight, derived from FDA-approved compounds using the python script fragmentizer. Distributed by the National Biomedical Computation Resource.
  • Desmond Absolute Solvation Free Energies Set. Set of 239 molecules used for Absolute Solvation Free Energy calculations, in Maestro, SMILES and SMARTS format along with the experimental and calculated absolute solvation free energies. Provided by Schrödinger.
  • NRDBSM. (Non Redundant Database of Small Molecules) is a database aimed specifically at virtual high throughput screening of small molecules. It has been developed giving special consideration to physicochemical properties and Lipinski’s rule of five. Provided by the Supercomputing Facility for Bioinformatics & Computational Biology, IIT Delhi.
  • Ligand Expo. Ligand Expo (formerly Ligand Depot) provides chemical and structural information about small molecules within the structure entries of the Protein Data Bank. Tools are provided to search the PDB dictionary for chemical components, to identify structure entries containing particular small molecules, and to download the 3D structures of the small molecule components in the PDB entry. A sketch tool is also provided for building new chemical definitions from reported PDB chemical components.
  • SuperLigands. Encyclopedia that is dedicated to a ligand oriented view of the protein structural space. The database contains small molecule structures occurring as ligands in the Protein Data Bank. SuperLigands integrates different information about drug-likeness or binding properties. A 3D superpositioning algorithm is implemented that allows to screen all ligands for possible scaffold hoppers as well as a 2D similarity screen for compounds based on fingerprints. Provided by harité Berlin – Structural Bioinformatics Group (SBG).
  • ChEBI. (Chemical Entities of Biological Interest). Freely available dictionary of molecular entities focused on ‘small’ chemical compounds. provided by the European Bioinformatics Institute.
  • KEGG DRUG. Comprehensive drug information resource for approved drugs in Japan, USA, and Europe unified based on the chemical structures and/or the chemical components, and associated with target, metabolizing enzyme, and other molecular interaction network information. Provided by the Kyoto Encyclopedia of Genes and Genomes.

Databases handling

  • Bingo. Relational database management system (RDBMS) data cartridge that provides fast, scalable, and efficient storage and searching solution for chemical information. Bingo integrates the chemistry into Oracle, Microsoft SQL Server and PostgreSQL databases. Its extensible indexing is designed to enable scientists to store, index, and search chemical moieties alongside numbers and text within one underlying relational database server. Free software. Distributed by GGA software.
  • JChem for Excel. Integrates structure handling and visualizing capabilities within a Microsoft Excel environment. Structures are fully supported within spreadsheets and be can viewed, edited, searched, resized, ordered, managed. Provided by ChemAxon.
  • ChemDiff. Indigo-based utility for finding duplications and visual comparison of two files containing multiple structures. SDF, SMILES, CML, MOLFILE input formats are supported. Files can contains large amount of molecules and ChemDiff was test on files with up to 1 million ones. Free and open-source. Distributed by GGA software.

Protein-ligand complexes databases

  • Protein DataBank (PDB). Databank of experimentally-determined structures of proteins, nucleic acids, and complex assemblies.
  • Binding MOAD (Mother Of All Database). Subset of the Protein Data Bank (PDB), containing a collection of well resolved protein crystal structures with clearly identified biologically relevant ligands annotated with experimentally determined binding data extracted from literature. Maintained by the university of Michigan.
  • Ligand Protein DataBase (LPDB). Collection of curated ligand-protein complexes, with 3D structures and experimental binding free energies. Maintained by the University of Michigan.
  • CREDO. Publicly available database of protein-ligand interactions, which represents contacts as structural interaction fingerprints and is completely scriptable through its application programming interface. CREDO includes implementation of molecular shape descriptors with ultrafast shape recognition, fragmentation of ligands in the Protein Data Bank, sequence-to-structure mapping and the identification of approved drugs. Developed by the Department of Biochemistry, University of Cambridge.
  • PDBbind. Collection of experimentally measured binding affinity data (Kd, Ki, and IC50) exclusively for the protein-ligand complexes available in the Protein Data Bank (PDB). All of the binding affinity data compiled in this database are cited from original references.
  • CSAR. (Community Structure-Activity Resource). Resource for Docking and Scoring Development. Provides experimental datasets of crystal structures and binding affinities for diverse protein-ligand complexes.
  • CCDC/Astex Validation set. The new CCDC/Astex test set consists of 305 protein-ligand complexes. All protonation states have been assigned by manual inspection. It is an extended version of the original GOLD validation test set.
  • SeRAPhiC. Data set of 53 high-quality protein-fragment complexes, filtered out from the Worldwide Protein Data Bank (wwPDB) and made publicly available.
  • AffinDB. Freely accessible database of affinities for protein-ligand complexes from the PDB.
  • Protein Ligand Database (PLD). Collection of protein ligand complexes extracted fom the PDB along with biomolecular data, including binding energies, Tanimoto ligand similarity scores and protein sequence similarities of protein-ligand complexes. Maintained by the University of Cambridge.
  • BindingDB. Public, web-accessible database of measured binding affinities, focusing chiefly on the interactions of protein considered to be drug-targets with small, drug-like molecules.
  • Ki Database. Provides information on the abilities of drugs to interact with an expanding number of molecular targets. The Ki database serves as a data warehouse for published and internally-derived Ki, or affinity, values for a large number of drugs and drug candidates at an expanding number of G-protein coupled receptors, ion channels, transporters and enzymes. Currently 55472 Ki values. Maintained by the NIMH Psychoactive Drug Screening Program.
  • SCORPIO. Free online repository of protein-ligand complexes which have been structurally resolved and thermodynamically characterised.
  • PDSP. Psychoactive Drug Screening Program. Provides screening of novel psychoactive compounds for pharmacological and functional activity at cloned human or rodent CNS receptors, channels, and transporters. Assays, Ki,…
  • BAPPL complexes set. 161 protein-ligand complexes with experimental and estimated binding free energies calculated with the BAPPL server.
  • DNA Drug complex dataset. Dataset of DNA-drug complexes consisting of 16 minimized crystal structures and 34 model-built structures, along with experimental affinities, used to validate PreDDICTA.
  • Binding Database. Public, web-accessible database of measured binding affinities, focusing chiefly on the interactions of protein considered to be drug-targets with small, drug-like molecules. Maintained by the Center for Advanced Research in Biotechnology, University of Maryland Biotechnology Institute.
  • Kuntz Protein Test Set. Set of 114 crystallographically determined protein-ligand structures used to test the docking program DOCK. Maintained by UCSF.

Target databases

  • TTD. (Therapeutic Target Database). Database to provide information about the known and explored therapeutic protein and nucleic acid targets, the targeted disease, pathway information and the corresponding drugs directed at each of these targets. Also included in this database are links to relevant databases containing information about target function, sequence, 3D structure, ligand binding properties, enzyme nomenclature and drug structure, therapeutic class, clinical development status. All information provided are fully referenced.

Pathway databases

  • STITCH. Resource to explore known and predicted interactions of chemicals and proteins. Chemicals are linked to other chemicals and proteins by evidence derived from experiments, databases and the literature. STITCH contains interactions for between 300,000 small molecules and 2.6 million proteins from 1133 organisms. Provided by the Beyer group of the Biotechnology Center TU Dresden.
  • SMPDB. (Small Molecule Pathway Database). Interactive, visual database containing more than 350 small molecule pathways found in humans. SMPDB is designed specifically to support pathway elucidation and pathway discovery in metabolomics, transcriptomics, proteomics and systems biology. All SMPDB pathways include information on the relevant organs, subcellular compartments, protein cofactors, protein locations, metabolite locations, chemical structures and protein quaternary structures. Provided by the Departments of Computing Science & Biological Sciences, University of Alberta.
  • Chemical structure representations

ChemDraw, MarvinSketch, ACD/ChemSketch, jsMolEditor, Marvin molecule editor and viewer, Ketcher, UCSF Chimera, Pymol, Swiss-PDB Viewer / DeepView, Daylight SMILES, InChI, Tripos Mol2, OpenBabel, Corina, Indigo, PoseView, DS Visualizer, BINANA, E-Babel, Corina online demo, Chemical Identifier Resolver, ChemMobi, ChemSpotlight, …

2D drawing

  • ChemDraw. Molecule editor developed by the cheminformatics company CambridgeSoft. For Windows and Mac.
  • MarvinSketch. Advanced chemical editor for drawing chemical structures, queries and reactions developed by ChemAxon. Exists as an applet.
  • ACD/ChemSketch. Molecule editor developed by ACD/Labs. Also available as freeware, with tools for 2D structure cleaning, 3D optimization and viewing, InChI generation and conversion, drawing of polymers, organometallics, and Markush structures. For Windows only.
  • JChem for Excel. Integrates structure handling and visualizing capabilities within a Microsoft Excel environment. Structures are fully supported within spreadsheets and be can viewed, edited, searched, resized, ordered, managed. Provided by ChemAxon.
  • JKluster. Tool of JChem for clustering, diversity calculations, and library comparisons based on molecular fingerprints and other descriptors. Useful in combinatorial chemistry, drug design, or other areas where a large number of compounds need to be analyzed. Provided by ChemAxon.
  • VLifeBase. Provides features to build a molecule from scratch using 2D Draw and conversion to 3D. The 3D editor allows addition, modification, replacement and deletion of atoms, bonds and groups, with Undo and Redo operations. Provided by VLife.
  • ISIS/Draw. Chemical structure drawing program for Windows, published by MDL Information Systems. Free of charge for academic and personal use.
  • ChemDoodle. Chemical structure environment with a main focus on 2D graphics and publishing to create media for structures, reactions and spectra. For Windows, Mac and Linux.
  • ChemDoodle Mobile. Free iPhone companion to ChemDoodle. ChemDoodle Mobile is a calculator for drawn organic structures. There are four main windows: Draw, Calculate, Spectra and Help. The Draw window shows a typical ChemDoodle sketcher, where you can draw and store your structures. The Calculate page calculates properties and the Spectra page simulates NMR spectra. All spectra are interactive. The Help page contains a thorough help guide. Provided by iChemLabs.
  • Chirys Draw. Application for drawing publication-quality molecular structures and reactions. Designed from the ground up for the iPad. Developed by Integrated Chemistry Design, Inc.
  • Chirys Sketch. Application for drawing publication-quality molecular structures and reactions, for iPhone and iPod Touch. Developed by Integrated Chemistry Design, Inc.
  • Mobile Molecular DataSheet. Allows viewing and editing chemical structure diagrams on an iPhone, iPod or iPad. Molecules are organized in collections of datasheets. Individual molecules, or whole datasheets, can be shared via iTunes or sent by email, using the standard MDL MOL and SDfile formats, which allows the data to be integrated into any external workflow. Provided by Molecular Materials Informatics, Inc.
  • Molprime+. Chemical structure drawing tool based on the unique sketcher from the Mobile Molecular DataSheet. Can send structure data via email, open structures from email or web, create graphical images or Microsoft Word documents with embedded structure graphics, calculate properties based on structures and use structures to search Mobile Reagents and ChemSpider. Provided by Molecular Materials Informatics, Inc.
  • Elemental. Chemistry sketch for iphone and ipad. Developed by Dotmatics Limited.
  • Accelrys Draw. Allows drawing and editing complex molecules, chemical reactions and biological sequences. provided by Accelrys.
  • PLT. Program for producing chemical drawings and outputting them in a variety of formats. For Windows.
  • JChemPaint. Free and open source editor and viewer for chemical structures in 2D. Exists as a Java stand alone application and two varieties of Java applet that can be integrated into web pages. Platform-independent.
  • BKchem. BKChem is a free open source chemical drawing program written in Python. Platform-independent.
  • MolSketch. Free open source molecular drawing tool for 2D molecular structures. Available for Windows, Mac and Linux.
  • JME Molecular Editor. Java applet which allows to draw / edit molecules and reactions (including generation of substructure queries) and to depict molecules directly within an HTML page. Editor can generate Daylight SMILES or MDL Molfile of created structures.
  • Chem4D. Molecular drawing tool. Includes assignment of systematic names to organic structures according to IUPAC nomenclature rules, and drawing of molecules from IUPAC names. For Windows and Mac. Distributed by ChemInnovation Software.
  • XDrawChem. Free open source software program for drawing chemical structural formulas, available for Windows, Unix, and Mac OS.
  • iMolecular Draw. Application that can view, edit and build molecules in 2D. For iPhone.
  • SketchEl. Free and open source interactive chemical molecule sketching tool, and molecular spreadsheet data entry application. Written in Java. Exists as an applet.
  • Chemtool. Free open source program for drawing chemical structures on Linux and Unix systems using the GTK toolkit under X11.
  • Bioclipse. Java-based, open source, visual platform for chemo- and bioinformatics based on the Eclipse Rich Client Platform (RCP).
  • CLiDE. Chemical Literature Data Extraction. Chemistry intelligent equivalent of Optical Character Recognition (OCR) software. Recognizes structures, reactions and text from scanned images of printed chemistry literature and transforms the ‘images’ into a ‘real structures’ that can then be input into databases.
  • Chrawler. Can scan all data sources, including local files, remote files on network, emails, web pages, SharePoint contents, etc., and find contained chemical structures, and make them structure-searchable (substructure, full-structure, similarity). Distributed by Scilligence.
  • Imago. Toolkit for 2D chemical structure image recognition. It contains a GUI program and a command-line utility, as well as a documented API for developers. Imago is completely free and open-source, while also available on a commercial basis. Distributed by GGA software.
  • Ego. Java GUI for Imago. Ego is completely free and open-source, while also available on a commercial basis. Distributed by GGA software.
  • Alter_ego. Command-line interface for Imago. Alter-Ego is completely free and open-source, while also available on a commercial basis. Distributed by GGA software.
  • OLN Chem4SharePoint. Makes it possible to draw, display and search chemical structures in SharePoint. Distributed by Scilligence.
  • ChemJuice. Molecular drawing software for iPhone. Developed by IDBS.
  • ChemJuice Grande. Molecular drawing software for iPad. Developed by IDBS.
  • MolPad. Free chemical structure drawing application. It can draw structures from scratch or load them from ChemSpider and modify them. Structures can be emailed in Molfile format. For Android.
  • DCE ChemPad. Free application to draw chemical structures and calculate molecular weight, molecular formula and to send the molfile. It shows the capabilities of the Dendro Chemical Editor control for Android to build chemistry-aware mobile applications. For Android.
  • Indigo-depict. Command-line molecule and reaction rendering utility. Free and open source. Distibuted by GGA software.

2D drawing online

  • jsMolEditor. Molecule Editor of JavaScript. Open source.
  • Marvin molecule editor and viewer. Java based chemical editor for drawing chemical structures. Includes unlimited structure based predictions for a range of properties (pKa, logD, name<>structure, etc.). Provided by ChemAxon.
  • Ketcher. Web-based chemical structure editor written in JavaScript. Free and open-source, but also available on a commercial basis. Distributed by GGA software.
  • ChemWriter. Chemical structure editor designed for use with Web applications. Distributed by Metamolecular.
  • Molinspiration WebME Molecule Editor. Allows creation and editing of molecules in browsers without Java support and without any plugins. The editor is based on a Web2.0 Ajax technology. WebME allows therefore web-based structure input also in institutions where Java applets are not allowed and offers complete platform compatibility. The actual molecule processing in WebME is based on the JMEPro editing engine running on a server. provided by Molinspiration.

3D viewers

  • UCSF Chimera. Open source, highly extensible program for interactive visualization and analysis of molecular structures and related data. Free of charge for academic, government, non-profit, and personal use. For Windows, Mac and Linux. Developed by the Resource for Biocomputing, Visualization, and Informatics, UCSF.
  • Pymol. Open source, user-sponsored, molecular visualization system written in Python. Distributed by DeLano Scientific LLC. For Windows, Mac and Linux.
  • Swiss-PDB Viewer / DeepView. Program for 3D visualization of macromolecules, allowing to analyze several proteins at the same time. Swiss-PdbViewer is tightly linked to SWISS-MODEL, an automated homology modeling server developed within the Swiss Institute of Bioinformatics (SIB).
  • Computer-Aided Drug-Design Platform using PyMOL. PyMOL plugins providing a graphical user interface incorporating individual academic packages designed for protein preparation (AMBER package and Reduce), molecular mechanics applications (AMBER package), and docking and scoring (AutoDock Vina and SLIDE).
  • Autodock Vina plugin for PyMOL. Allows defining binding sites and export to Autodock and VINA input files, doing receptor and ligand preparation automatically, starting docking runs with Autodock or VINA from within the plugin, viewing grid maps generated by autogrid in PyMOL, handling multiple ligands and set up virtual screenings, and set up docking runs with flexible sidechains.
  • Dehydron. A dehydron calculator plugin for PyMOL. This plugin calculates dehydrons and display them onto the protein structure.
  • pymacs. Python module for dealing with structure files and trajectory data from the GROMACS molecular dynamics package. It has interfaces to some gromacs functions and uses gromacs routines for command line parsing, reading and writing of structure files (pdb,gro,…) and for reading trajectory data (only xtc at the moment).
  • PyRosetta. Interactive Python-based interface to the Rosetta molecular modeling suite. It enables users to design their own custom molecular modeling algorithms using Rosetta sampling methods and energy functions.
  • Visual Molecular Dynamics (VMD). Free open source molecular visualization program for displaying, animating, and analyzing large biomolecular systems using 3-D graphics and built-in scripting. For MacOS X, Unix, or Windows. Developed by the NIH resource for macromolecular modeling and bioinformatics, University of illinois.
  • ePMV. (embedded Python Molecular Viewer). Free, open-source plug-in that runs molecular modeling software directly inside of professional 3D animation applications (hosts, i.e. Blender, Cinema4D and Maya 2011) to provide simultaneous access the capabilities of all of the systems. Developed by the Scripps Research Institute.
  • Jmol. Open source Java viewer for chemical structures in 3D.
  • GLmol. Free and open source 3D molecular viewer based on WebGL and Javascript. GLmol runs on newer versions of Firefox, Chrome, Safari or Opera. Internet Explorer is not supported. GLmol also runs on Sony Ericsson’s Android devices which support WebGL and WebGL enabled safari in iOS.
  • DS Visualizer. Free 3D visualizer of Discovery Studio. Allows sequence handling and, 2D or 3D charting. Creates 2D ligand-receptor interaction diagrams. Distributed by Accelrys. DS Visualizer ActiveX Control allows visualizing and interacting with molecules in Microsoft Office documents and Internet Explorer. For Windows and Linux.
  • OpenAstexViewer. Free open source java molecular graphics program that assists in structure based drug design. It can be used as an Applet in a web page or as a desktop application. Provided by Astex Therapeutics. For Windows, linux and Mac.
  • ICM-Browser. Free molecular visualization program for displaying proteins, DNA and RNA, and multiple sequence alignments. Allows saving interactive 3D files to display on the web or in PowerPoint. Distributed by Molsoft. For Windows, Mac and linux. Exist in a Pro version.
  • Jamberoo. Free open source program for displaying, analyzing, editing, converting, and animating molecular systems (former JMolEditor). For Windows, Mac and Linux.
  • YASARA View. Free molecular visualization program for displaying macromolecules, building molecules, multiple sequence alignments. Can be complemented by YASARA Model. Provided by YASARA.
  • QuteMol. Open source (GPL), interactive, high quality molecular visualization system. QuteMol exploits the current GPU capabilites through OpenGL shaders to offers an array of innovative visual effects. QuteMol visualization techniques are aimed at improving clarity and an easier understanding of the 3D shape and structure of large molecules or complex proteins. Developed by the Visual Computing Lab at ISTI-CNR, Italy.
  • CueMol. Program for the macromolecular structure visualization (CueMol was formerly called “Que”). CueMol aims to visualize the crystallographic models of macromolecules with the user-friendly interfaces. Currently supported files are molecular coordinates (PDB format), electron density (CCP4, CNS , and BRIX formats), MSMS surface data, and APBS electrostatic potential map.
  • TexMol. Molecular visualization and computation package. Free and open source software.
  • Chil2 Viewer. Visualization tool and graphical user interface of the Chil2 suite, with analysis tools, database integration and ruby interface. Open for general research.
  • VEGA ZZ. Visualization application and molecular modeling toolkit (Molecular mechanics and dynamics, structure-based screening). Free for non-profit academic uses. Provided by the Drug Design Laboratory of the University of Milano.
  • BALLView. Standalone molecular modeling and visualization application. Provides a framework for developing molecular visualization functionality. Can be used as the visualizaion component of BALL. Free and opensource. For Windows, Mac and Linux.
  • Avogadro. Free, open source, molecule editor and visualizer designed for cross-platform use in computational chemistry, molecular modeling, bioinformatics, materials science, and related areas.
  • RasMol. Program for molecular graphics visualisation.
  • RasTop. Free open source molecular visualization software adapted from the program RasMol. RasTop wraps a user-friendly graphical interface around the “RasMol molecular engine”. Developed for educational purposes and for the analysis of macromolecules at the bench. For Windows and Linux.
  • Qmol. Program for viewing molecular structures and animating molecular trajectories. Distributed by DNASTAR.
  • CheVi. Program for viewing molecular structures providing an interface to eHiTS. For linux. Distributed freely by SimBioSys.
  • Cn3D. Visualization tool for biomolecular structures, sequences, and sequence alignments. Maintained and distributed by the NCBI. For Windows, Mac and Linux.
  • Bodil. Free, modular, multi-platform software package for biomolecular visualization and modeling. Bodil aims to provide easy three-dimensional molecular graphics closely integrated with sequence viewing and sequence alignment editing.
  • COSMOS Viewer. Free software for presentation of molecules.
  • BARISTA. BARISTA visualization functions create, display, and manipulate 3D depictions of molecular structures based on results computed by molecular computation programs such as Conflex, and are designed specifically to facilitate the analysis of these results. For Windows and Linux.
  • BioAdviser. Visualization tool for biomolecular structures and small molecules.
  • iMolview. Application to browse and view in 3D protein and DNA structures from Protein Data Bank, and drug molecules from DrugBank For iPhone and iPad. Provided by Molsoft.
  • PyMOL on the iPad.. High-performance 3D molecular visualizer, designed from the ground up for the iPad. it can search and download data from the PDB, PubChem, Dropbox, or an own secure custom PyMOL enterprise server. Provided by Schrödinger.
  • RCSB PDB.. The RCSB Protein Data Bank (PDB) mobile app is the official mobile app of the RCSB PDB. It provides fast, on-the-go access to the RCSB PDB resources. The app enables the general public, researchers and scholars to search the Protein Data Bank and visualize protein structures using either a WiFi or cellular data connection.
  • Ball&Stick. High-quality molecular visualization app for the iPad, iPhone and iPod Touch. Provided by MolySym.
  • CueMol for iOS. Interactive macromolecular viewer for structural biologists. CueMol viewer allows the users to open and view the scene files made by the desktop version of CueMol, and the Protein Data Bank (PDB) format files, as well.
  • CMol. Interactive 3D molecular viewer designed specifically for the iPad, iPhone and iPod touch. CMol allows the user to open and view PDB files with complete control over the representations and colours used for individual chains, residues and atoms.
  • Molecules. Free application for iPhone and iPad, for viewing three-dimensional renderings of molecules and manipulating them using your fingers. You can rotate the molecules by moving your finger across the display, zoom in or out by using two-finger pinch gestures, or pan the molecule by moving two fingers across the screen at once. These structures can be viewed in both ball-and-stick and spacefilling visualization modes.
  • iMolecular Builder. The IMoleBuilder is an application that can view, edit and build molecules in 3D. For iPhone.
  • iPharosDreams. Molecular visualization app for iPad to perform in-silico drug discovery. Downloads protein structure files from Protein Data Bank, displays 3D molecules, touch, rotation, zoom in/out. Hierarchy structure of molecules is shown with a table that select components in a protein and related things. It can generate pharmacophores and analyze 3D protein-ligand interaction of biological macromolecules for in-silico drug discovery. Allows selecting a ligand from a protein and generate a binding site from the selected ligand. Can generate receptor based pharmacophores and get inspiration. Developed by EQUISnZAROO CO., LTD.
  • Jmol Molecular Visualization. Free Jmol for Android tablets.
  • NDKmol. Free molecular viewer for Android.
  • Molecule Viewer 3D. Opens most common 3D molecule file formats saved on a SD card or found in a library of 243 included molecules. For Android.
  • 3D Molecule View. 3D molecule viewer. For Android.
  • Atomdroid. Free computational chemistry tool. It can be used as a molecular viewer/builder and contains local optimization and Monte Carlo simulation features. For Android.
  • Atom 3D. Free application to visualize molecules and crystal structures in 3D using the touchscreen to rotate and zoom. Includes 19 sample structures. Supports XYZ files and some protein data bank (PDB) files. For Android.
  • PDBs. Free application for molecular graphics visualization from PDB files. For Android.
  • PDB View 3D. Application for molecular graphics visualization from PDB files. For Android.

Definitions and syntax of file formats

  • Daylight SMILES. SMILES (Simplified Molecular Input Line Entry System) is a line notation (a typographical method using printable characters) for entering and representing molecules and reactions.
  • InChI. (IUPAC International Chemical Identifier) is a string of characters capable of uniquely representing a chemical substance. It is derived from a structural representation of that substance in a way designed to be independent of the way that the structure was drawn (thus a single compound will always produce the same identifier). It provides a precise, robust, IUPAC approved tag for representing a chemical substance.
  • Tripos Mol2. Complete description of the Mol2 file format (.mol2).
  • PDB format. Complete description of the PDB file format (.pdb).
  • SDF format. Complete description of the SDF file format (.sdf).
  • SMARTS format. SMARTS Tutorial by Daylight.
  • OpenSMILES. Community sponsored open-standards version of the SMILES language for chemistry. OpenSMILES is part of the Blue Obelisk community.

File format Converters

  • OpenBabel. Free open source chemical expert system mainly used for converting chemical file formats. For Windows, Unix, and Mac OS.
  • Corina. Generates 3D structures for small and medium sized, drug-like molecules. Distributed by Molecular Networks.
  • Indigo. Universal organic chemistry toolkit, containing tools for end users, as well as a documented API for developers. Free and open-source, but also available on a commercial basis. Distributed by GGA software.
  • Indigo-depict. Command-line molecule and reaction rendering utility. Free and open source. Distibuted by GGA software.
  • Indigo-cano. Command-line canonical SMILES generator. Free and open source. Distibuted by GGA software.
  • Indigo-deco. Command-line program for R-Group deconvolution. Free and open source. Distibuted by GGA software.
  • OMEGA. (Conformer Ensembles Containing Bioactive Conformations). Converts from 1D or 2D to 3D using distance bounds methods, with a focus on reproducing the bioactive conformation. Developed by OpenEye.
  • LigPrep. 2D to 3D structure conversions, including tautomeric, stereochemical, and ionization variations, as well as energy minimization and flexible filters to generate ligand libraries that are optimized for further computational analyses. Distributed by Schrodinger.
  • CACTVS. Universal scriptable toolkit for chemical information processing. Used by PubChem. Maintained and distributed by Xemistry. Free for academic.
  • ChemDiff. Indigo-based utility for finding duplications and visual comparison of two files containing multiple structures. SDF, SMILES, CML, MOLFILE input formats are supported. Files can contains large amount of molecules and ChemDiff was test on files with up to 1 million ones. Free and open-source. Distributed by GGA software.
  • OSRA. (Optical Structure Recognition Application). Utility designed to convert graphical representations of chemical structures, as they appear in journal articles, patent documents, textbooks, trade magazines etc. OSRA can read a document in any of the over 90 graphical formats parseable by ImageMagick – including GIF, JPEG, PNG, TIFF, PDF, PS etc., and generate the SMILES or SDF representation of the molecular structure images encountered within that document. Free and open source. Developed by the Frederick National Laboratory for Cancer Research, NIH.
  • MayaChemTools. Collection of Perl scripts, modules, and classes to support day-to-day computational chemistry needs. Free software, open source. Provided by Manish Sud.
  • VLife Engine. Engine module of VLifeMDS containing basic molecular modeling capabilities such as building, viewing, editing, modifying, and optimizing small and arge molecules. Fast conformer generation by systematic and Monte-carlo methods. Provided by VLife.
  • SMART. (Small Molecule Atomtyping and Rotatable Torsion assignment) automatically identifies and labels the rotatable bonds of the ligands and assigns AMBER atom types. SMART is the module used to prepare ligand structures in a modified MOL2 format for use by FITTED. Part of the Molecular FORECASTER package and FITTED Suite. Free for an academic site license (excluding cluster).
  • ProCESS. (Protein Conformational Ensemble System Setup). Prepares protein files to be used with FITTED, by assigning the advanced residue names, advanced hydrogen names, atom types, and charges for the protein. Part of the Molecular FORECASTER package and FITTED Suite. Free for an academic site license (excluding cluster).
  • SPORES. (Structure PrOtonation and REcognition System). Structure recognition tool for automated protein and ligand preparation. SPORES generates connectivity, hybridisation, atom and bond types from the coordinates of the molecule`s heavy atoms and hydrogen atoms to the structure. The protonation can either be done by just adding missing hydrogen atoms or as a complete reprotonation. SPORES is able to generate different protonation states, tautomers and stereoisomers for a given structure. Developed by the Konstanz university.
  • PREPARE. (Protein Rotamers Evaluation and Protonation based on Accurate Residue Energy). Tool for protein preparation and optimization. Part of the Molecular FORECASTER package and FITTED Suite. Free for an academic site license (excluding cluster).
  • DG-AMMOS. Program to generate 3D conformation of small molecules using Distance Geometry and Automated Molecular Mechanics Optimization for in silico Screening. Freely distributed by the University of Paris Diderot.
  • Key3D. Molecular modeling tool to convert 2D structures (chemical structural formula) of compounds drawn by ISIS-Draw or ChemDraw to 3D structures with additional information on atomic charge etc. Distributed by IMMD.
  • CONFLEX. Software for searching and analyzing the conformational space of small and large molecules.
  • JOElib. Cheminformatics library mainly used for conversion of file formats. Written in Java. For Windows, Unix, and Mac OS.
  • CDK (Chemistry Development Kit). LGPL-ed library for bio- and cheminformatics and computational chemistry written in Java. Opensource.
  • MolEngine. .NET Cheminformatics Toolkit completely built on Microsoft .NET platform. By using Mono, MolEngine can run on other platform, such as Mac, Linux, iPad. Distributed by Scilligence.
  • Indigo. Universal organic chemistry toolkit. Free and opensource. Provided by GGA.
  • ChemDiff. Indigo-based utility for finding duplications and visual comparison of two files containing multiple structures. SDF, SMILES, CML, MOLFILE input formats are supported. Provided by GGA.
  • RDKit. Collection of cheminformatics and machine-learning software written in C++ and Python.
  • Mol2Mol. Molecule file manipulation and conversion program.
  • Fconv. Molecule file manipulation and conversion program.
  • smi23d. Consists of two programs that can be used to convert one or more SMILES strings to 3D. For Mac and Linux. Also exists as a web service.
  • Scaffold Hunter. JAVA-based software tool for exploring the chemical space by enabling generation of and navigation in a scaffold tree hierarchy annotated with various data. The graphical visualization of structural relationships allows to analyze large data sets, e.g., to correlate chemical structure and biochemical activity. Free open source software developed and supported by the Chair of algorithm Engineering at Technical University Dortmund and the Department of Chemical Biology at Max-Planck Institute for Molecular Physiology Dortmund.
  • ScaffoldTreeGenerator. Java-based program which generates the scaffold tree database independently of Scaffold Hunter. Free open source software developed and supported by the Chair of algorithm Engineering at Technical University Dortmund and the Department of Chemical Biology at Max-Planck Institute for Molecular Physiology Dortmund.
  • Strip-it. Program to extract scaffolds from organic drug-like molecules by ‘stripping’ away sidechains and representing the remaining structure in a condensed form. Open source software distributed by Silicos.
  • fragmentizer. Free and open source python script that can decompose PDBs of small-molecule compounds into their constituent fragments. Developed by the National Biomedical Computation Resource.
  • Epik. Enumerates ligand protonation states and tautomers in biological conditions. Distributed by Schrodinger.
  • iBabel. iBabel is an alternative graphical interface to Open Babel for Macintosh OS X.
  • Vconf. 2D-to-3D conversion and conformational search program which accepts an SD file of drug-like compounds in arbitrary initial conformations and uses a unique, symmetry-aware output filter to ensure that no conformations are repeated in the output. Available as a command-line driven program. For Linux or Windows. Distributed by VeraChem.
  • Vcharge. Calculates accurate “ab initio-like” partial atomic charges for an SDfile of drug-like compounds in ~0.1seconds/compound and outputs an SDfile with the calculated partial charges embedded in an easily parsable datablock. Exists as a web service. For Linux or Windows. Distributed by VeraChem.
  • PerlMol. Collection of perl modules providing objects and methods for representing molecules, atoms, and bonds in Perl; doing substructure matching; and reading and writing files in various formats.
  • The SDF Toolkit in Perl 5. The purpose of this SDF toolkit is to provide functions to read and parse SDFs, filter, and add/remove properties.

Analysis of ligand-protein interactions

  • PoseView. Automatically generates 2D structure-diagrams of protein-ligand complexes (png, svg and pdf) provided as 3D-input. Such input may come directly from crystal structures or be computed for example by a docking program. PoseView images are available for the majority of PDB-structures on the PDB web site. Developed by the University of Hamburg and distributed by BioSolveIT.
  • DS Visualizer. Free 3D visualizer of Discovery Studio. Allows sequence handling and, 2D or 3D charting. Creates 2D ligand-receptor interaction diagrams. Distributed by Accelrys. DS Visualizer ActiveX Control allows visualizing and interacting with molecules in Microsoft Office documents and Internet Explorer. For Windows and Linux.
  • BINANA. (BINding ANAlyzer). Python-implemented algorithm for analyzing ligand binding. The program identifies key binding characteristics like hydrogen bonds, salt bridges, and pi interactions. As input, BINANA accepts receptor and ligand files in the PDBQT format. Allows visualization with VMD. Developed by the National Biomedical Computation Resource.

Web services

  • E-Babel. Online version of OpenbBabel. Maintained by the Virtual Computational Chemistry Laboratory.
  • Corina online demo. Online demo of CORINA. Generates 3D coordinates from SMILES.
  • Chemical Identifier Resolver. Converts a given structure identifier into another representation or structure identifier, using CACTVS. May give the name of a given molecule from SMILES of InChi, thanks to a database of 68 million chemical names linked to 16 million unique structure records.
  • ChemSpider’s InChI resolver. The InChI Resolver provides online access to a series of tools supporting the generation and look-up of InChIStrings and InChIKeys. Provided by ChemSpider.
  • VEGA WE. Web server for file translation tool, properties and surface calculation. Provided by the Drug Design Laboratory of the University of Milano.
  • PDB Hydrogen Addition. Tool to add the hydrogen in a given PDB (for protein, DNA and drugs).
  • DG-AMMOS. Generates single 3D conformer for small compound.
  • Frog2. FRee Online druG conformation generation.
  • e-LEA3D. Draw a molecule by using the ACD applet (v.1.30) and generate 3D coordinates by using the program Frog.
  • MolEdit. Web server for 2D molecular editor & 3D structure optimization. Provided by the Drug Design Laboratory of the University of Milano.
  • ProBuilder. Protein/peptide builder from 1D to 3D. Provided by the Drug Design Laboratory of the University of Milano.
  • Online SMILES Translator and Structure File Generator. Translates SMILES into SDF, PDB of MOL formats, possibly generating 3D coordinates.
  • smi23D web service. Translates SMILES strings or a URL to a SMILES file and get back the 3D coordinates in SDF. users can get the SDF file by typing directly the SMILES in the web browser, e.g. http://rest.rguha.net/threed/d3.py/get3d?smiles=c1ccccc1
  • PoseView. Automatically generates 2D structure-diagrams of protein-ligand complexes provided as 3D-input. Such input may come directly from crystal structures or be computed for example by a docking program. Developed by the University of Hamburg and distributed by BioSolveIT.
  • LCT. The Ligand Contact Tool calculates contacts between protein and ligand atoms, several parameters are available (distance cut-off, Van Der Waals radii usage, etc). Queries acepted are uploadable PDB format file or PDB accession code. Provided by the Structural Computational Biology Group of the Spanish national Cancer Research Centre.
  • SimiCon. Identifies the equivalent protein-ligand atomic contacts between Reference and Target complexes. Results are shown as text, tables and 3D interactive graphics
  • WWMM Web Services. Portal providing services which are parts of World Wide Molecular Matrix. Includes Openbabel online, InChI generation from MOL/CLM file, CMLRSS feed generation from a CML file, formulation generation and molecular weight calculation for a molecule in CML.
  • Vcharge. Calculates accurate “ab initio-like” partial atomic charges for an SDfile of drug-like compounds in ~0.1seconds/compound and outputs an SDfile with the calculated partial charges embedded in an easily parsable datablock. Provided by VeraChem.
  • Smi2Depict. Webservice to generate 2D images from SMILES.
  • GIF/PNG-Creator. GIF/PNG-Creator for 2D Plots of Chemical Structures from SMILES or structure files, using CACTVS. Maintained by the National Cancer institute, NIH.
  • depict. Webservice using the molconvert tool of ChemAxon to generate 2D images from SMILES.
  • SMARTSviewer. Webservice to visualize 2D images from SMARTS.
  • OSRA web service. (Optical Structure Recognition Application). Web service designed to convert graphical representations of chemical structures, as they appear in journal articles, patent documents, textbooks, trade magazines etc. OSRA can read a document in any of the over 90 graphical formats parseable by ImageMagick – including GIF, JPEG, PNG, TIFF, PDF, PS etc., and generate the SMILES or SDF representation of the molecular structure images encountered within that document. Free and open source. Developed by the Frederick National Laboratory for Cancer Research, NIH.

Others

  • ChemMobi. ChemMobi is a tool for Chemists, Biochemists and anyone else interested in chemical structures, chemical sourcing, chemical properties and safety information. For iPhone.
  • ChemSpotlight. ChemSpotlight is a plugin for Mac OS X 10.5 and later, which reads common chemical formats and provides searching and preview in the Finder. ChemSpotlight reads common chemical file formats using the Open Babel chemistry library. Spotlight can then index and search chemical data: molecular weights, formulas, SMILES, InChI, fingerprints, etc. Developed by Geoffrey Hutchison. Free and open source.

Molecular Modeling

CHARMM, GROMACS, Amber, SwissParam, Dundee PRODRG2 Server, PDB2PQR Server, SwissSideChain, …

Software

  • CHARMM. (Chemistry at HARvard Macromolecular Mechanics). Package of molecular simulation programs, including source code and demos.
  • GROMACS. (GROningen MAchine for Chemical Simulations). Free open source molecular dynamics simulation package.
  • Amber. (Assisted Model Building with Energy Refinement). Package of molecular simulation programs, including source code and demos.
  • AmberTools. AmberTools consists of several independently developed packages that work well by themselves, and with Amber itself. It contains NAB (build molecules; run MD or distance geometry, using generalized Born, Poisson-Boltzmann or 3D-RISM implicit solvent models), antechamber and MCPB (create force fields for general organic molecules and metal centers), tleap and sleap (Basic preparation program for Amber simulations), sqm (semiempirical and DFTB quantum chemistry program), pbsa (Performs numerical solutions to Poisson-Boltzmann models), 3D-RISM (Solves integral equation models for solvation), ptraj and cpptraj (structure and dynamics analysis of trajectories), MMPBSA.py and amberlite (Energy-based analyses of MD trajectories)
  • NAMD. (NAnoscale Molecular Dynamics). Free parallel molecular dynamics code designed for high-performance simulation of large biomolecular systems. Based on Charm++ parallel objects.
  • aMD. (accelerated Molecular Dynamics). enhanced-sampling method that improves the conformational space sampling by reducing energy barriers separating different states of a system. Distributed by the National Biomedical Computation Resource.
  • MATCH. (Multipurpose Atom-Typer for CHARMM). Toolset of program libraries collectively titled multipurpose atom-typer for CHARMM (MATCH) for the automated assignment of atom types and force field paramters for molecular mechanics simulation of organic molecules. Developed by the Brooks lab, Michigan university.
  • Desmond. Package to perform high-speed molecular dynamics simulations of biological systems on conventional computer clusters. Developed at D. E. Shaw Research.
  • LAMMPS. Program for molecular dynamics. LAMMPS has potentials for soft materials (biomolecules, polymers), solid-state materials (metals, semiconductors) and coarse-grained or mesoscopic systems.
  • MOLARIS. MOLARIS incorporates the methodologies of the former packages ENZYMIX and POLARIS. ENZYMIX is a macromolecular simulation program designed to study the functions of proteins ranging from ligand binding to free energy profiles of enzymatic reactions using the Empirical Valence Bond (EVB) approach and the Free Energy Perturbation (FEP) method. POLARIS is a fast converging computational software based on the Protein Dipoles-Langevin Dipoles (PDLD) approach, it is used for the calculation of free energies and electrostactic properties of molecules and macromolecules in solution through the evaluation of the permanent dipoles, induce dipoles, charges, dispersion contributions and hydrophobicity. Provided by the Warshel’s group at the university of Southern California.
  • OPENMD. Open source molecular dynamics to simulate liquids, proteins, nanoparticles, interfaces, and other complex systems using atom types with orientational degrees of freedom (e.g. sticky atoms, point dipoles, and coarse-grained assemblies).
  • ORAC. Free open source program for Moleuclar Dynamics simulations. Maintained by the Florence university, Italy.
  • AMMP VE. (Another Molecular Mechanics Program). Full-featured molecular mechanics, dynamics and modelling program that can manipulate both small molecules and macromolecules including proteins, nucleic acids and other polymers. Uses the VEGA ZZ interface. For MS Windows and Linux. Provided by the Drug Design Laboratory of the University of Milano.
  • ACEMD (Accelerating bio-molecular simulations). Production bio-molecular dynamics (MD) software running on graphics processing units (GPUs) on NVIDIA graphics cards. ACEMD reads CHARMM/NAMD and AMBER input files. Distributed by Acellera. Free for 1 year for academic.
  • CNS (Crystallography & NMR System). Provides a flexible multi-level hierachical approach for the most commonly used algorithms in macromolecular structure determination.
  • Adun molecular simulation. Free biomolecular simulator developed at the Computational Biophysics and Biochemistry Laboratory, a part of the Research Unit on Biomedical Informatics of the UPF. It is distributed under the GNU General Public License.
  • Tinker. Free, complete and general package for molecular mechanics and dynamics, with some special features for biopolymers.
  • Force Field Explorer. Graphical user interface to the TINKER suite of molecular modeling tools.
  • CHARMm. Commercial version of CHARMM with multiple graphical front ends.
  • MacroModel. Commercial program for molecular modeling. Distributed by Schrodinger.
  • MOIL. Public Domain Molecular Modeling Software, including energy calculations, energy minimization, molecular dynamics. Comes with a visualization program (zmoil) for graphic display of individual structures, dynamics, reaction paths and overlay of multiple structures, read PDB CRD DCD and (MOIL specific) PTH formatted files. For Windows, Mac and Linux.
  • APBS. Adaptive Poisson-Boltzmann Solver (APBS) is a software for evaluating the electrostatic properties of nanoscale biomolecular systems.
  • iAPBS. C/C++/Fortran interface to APBS. This interface enables access to most of APBS capability from within any C/C++ or Fortran code. In addition to the reference implementation, iAPBS/CHARMM, iAPBS/NAMD and iAPBS/Amber modules are also available. These modules extend CHARMM, NAMD and Amber functionality with APBS routines for electrostatic calculations. Provided by the McCammon Group, UCSD.
  • Chemsol. Program to calculate solvation energies by using Langevin Dipoles (LD) model of the solvent and ab initio calculations. Also exists as a web service. Provided by the Warshel’s group at the university of Southern California.
  • Abalone. General purpose molecular modeling program focused on molecular dynamics of biopolymers and molecular graphics. In addition, it can interact with external quantum chemical programs (NWChem, CP2K and PC GAMESS/Firefly. Provided by Agile Molecule.
  • Ascalaph. General purpose molecular modeling suite that performs quantum mechanics calculations for initial molecular model development, molecular mechanics and dynamics simulations in the gas or in condensed phase. It can interact with external molecular modeling packages (MDynaMix, NWChem, CP2K and PC GAMESS/Firefly). Provided by Agile Molecule.
  • HyperChem. Provides computational methods including molecular mechanics, molecular dynamics, and semi-empirical and ab-initio molecular orbital methods, as well as density functional theory.
  • iHyperChem. Limited version of Professional HyperChem. This Level 1 version of iHyperChem allows creating and manipulating molecular systems and explore their structure. It also allows WiFi access to any Professional HyperChem server so that molecules, computations, and results can be transferred between the mobile client (iPhone or iPad) and the server. Provided by HyperChem.
  • iHyperChem Free Version. Free Version of iHyperChem for iPad. Provided by HyperChem.
  • Spartan. Provides computational methods including molecular mechanics, quantum mechanics, properties calculations (LogP, ovality, etc…), quantification of structural alignment using structure, chemical funtion descriptors or pharmacophore model, etc… Developed by Wavefunction, Inc.
  • iSpartan. iSpartan is a versatile app for molecular modeling on the iPad, iPhone, and iPod Touch. Molecules are created by two-dimensional sketching and converted into a three-dimensional structure. Low-energy conformations can then be calculated and their geometries be queried. A database of 5,000 molecules (a subset of the Spartan Spectra and Properties Database, SSPD) can furthermore be accessed to obtain NMR and IR spectra, molecular orbitals, electrostatic potential maps, and other atomic and molecular properties. The database can be searched for substructures. Developed by Wavefunction, Inc.
  • YASARA Dynamics. Adds support for molecular simulations to YASARA View/Model, Using the NOVA, YAMBER or AMBER force fields like AMBER. Provided by YASARA.
  • Build model. Tool for creating protein models and their preparation for docking. Refine raw protein structure, add missing sidechains, assign protonation states of side chains at given pH, add missing hydrogen atoms, reconstruct crystallographically-related protein subunits and extract a reference ligand from the structure. Distributed by Moltech. For Windows and linux.
  • Pdbfil. Automatically processes the protein coordinate data obtained from PDB for molecular calculations. Adds missing atoms, deletes unnecessary hetero-residues and water molecules, adds and optimizes hydrogen atoms. Atomic attributions like atomic charge or molecular force-field type are also automatically. Distributed by IMMD.
  • Protein Preparation Wizard. Tool for correcting common structural problems and creating reliable, all-atom protein models. Distributed by Schrodinger.
  • BALL. Biochemical Algorithms Library. Application framework in C++ designed for rapid software prototyping in the field of Computational Molecular Biology and Molecular Modeling. It provides an extensive set of data structures as well as classes for Molecular Mechanics, advanced solvation methods, comparison and analysis of protein structures, file import/export, and visualization. Free and opensource.
  • MMTSB. Multiscale Modeling Tools for Structural Biology. Provides a collection of perl scripts for Structure preparation, Structure analysis, All-Atom Modeling, SICHO Lattice Modeling, Replica Exchange Sampling, Ensemble Computing and Structure Prediction.
  • Computer-Aided Drug-Design Platform using PyMOL. PyMOL plugins providing a graphical user interface incorporating individual academic packages designed for protein preparation (AMBER package and Reduce), molecular mechanics applications (AMBER package), and docking and scoring (AutoDock Vina and SLIDE).
  • pymacs. Python module for dealing with structure files and trajectory data from the GROMACS molecular dynamics package. It has interfaces to some gromacs functions and uses gromacs routines for command line parsing, reading and writing of structure files (pdb,gro,…) and for reading trajectory data (only xtc at the moment).
  • PyRosetta. Interactive Python-based interface to the Rosetta molecular modeling suite. It enables users to design their own custom molecular modeling algorithms using Rosetta sampling methods and energy functions.

Web Services

  • SwissParam. Provides topology and parameters for small organic molecules compatible with the CHARMM all atoms force field, for use with CHARMM and GROMACS.
  • Dundee PRODRG2 Server. Converts coordinates for small molecules in PDB format to the following topology formats: GROMOS, GROMACS, WHAT IF, REFMAC5, CNS, O, SHELX, HEX and MOL2.
  • PDB2PQR Server. Web server to convert PDB files into PQR files and perform an APBS calculation. Protein pKa are calculated using PROPKA.
  • PROPKA. Web server to calculate pKa of protein titratable functions.
  • PropKa. Web server to calculate pKa of protein titratable functions using PROPKA. Provided by the Drug Design Laboratory of the University of Milano.
  • H++. Web server to compute pK values of ionizable groups in macromolecules and adds missing hydrogen atoms according to the specified pH of the environment.
  • PDB_Hydro. Provides tools for mutating (change side-chains of a PDB file automatically, repair missing side-chains in a PDB file, construct polar hydrogen atoms and assig partial charges for electrostatic calculations) and solvating PDB files.
  • POLYVIEW-MM. Web-based platform for animation and analysis of molecular simulations. Enables animation of trajectories generated by molecular dynamics and related simulation techniques, as well as visualization of alternative conformers, e.g. obtained as a result of protein structure prediction methods or small molecule docking.
  • CLICK. Web server for superimposing the 3D structures of any pair of biomolecules (proteins, DNA, RNA, etc.). The server makes use of the Cartesian coordinates of the molecules with the option of using other structural features such as secondary structure, solvent accessible surface area and residue depth to guide the alignment. Help establishing protein relationships by detecting similarities in structural subdomains, domains and topological variants or to recognize conformational changes that may have occurred in structural domains or subdomains in one structure with respect to the other.
  • SLITHER. Web server for generating contiguous conformations of substrate molecules entering into deep active sites of proteins or migrating across membrane transporters. Predicts whether a substrate molecule can crawl through an inner channel or a half-channel of proteins across surmountable energy barriers.
  • R.E.D. Server. Web service designed to automatically derive RESP and ESP charges, and to build force field libraries for new molecules/molecular fragments.
  • Chemsol web service. Web service for the calculations of solvation free energies using the Langevin Dipoles (LD) solvation model, in which the solvent is approximated by polarizable dipoles fixed on a cubic grid.Also exists as a standalone program. Provided by the Warshel’s group at the university of Southern California.
  • MovieMaker. Web server that allows short (~10 sec), downloadable movies to be generated of protein dynamics. It accepts PDB files or PDB accession numbers as input and automatically outputs colorful animations covering a wide range of protein motions and other dynamic processes (simple rotation, morphing between two end conformers, short-scale, picosecond vibrations, ligand docking, protein oligomerization, mid-scale nanosecond (ensemble) motions and protein folding/unfolding). Note: MovieMaker is not a molecular dynamics server and does not perform MD calculations. Provided by the University of Alberta, Canada.
  • Superpose. Protein superposition server, using a modified quaternion approach. From a superposition of two or more structures, it generates sequence alignments, structure alignments, PDB coordinates, RMSD statistics, Difference Distance Plots, and interactive images of the superimposed structures. Provided by the University of Alberta, Canada.

Databases

  • SwissSideChain. Structural and molecular mechanics database of hundreds of non-natural amino-acid sidechains that can be used to study in silico their insertion into natural peptides or proteins. Topologies and parameters are provided for use with CHARMM and GROMACS. Provided UCSF Chimera and Pymol plugins allow mutating any residue of a PDB structure into one of the non-natural sidechains of the SwissSidechain database, and choose the most approtiate rotamer based on their frequency in the predicted rotamer library and possible clashes with the target
  • Homology Modeling

Modeller, I-TASSER, LOMETS, SWISS-MODEL, SWISS-MODEL Repository, Robetta, …

Software

  • Modeller. Software for producing homology models of protein tertiary structures, using a technique inspired by nuclear magnetic resonance known as satisfaction of spatial restraints. Maintained by Andrej Sali at the University of California, San Francisco. Free for academic use. Graphical user interfaces and commercial versions are distributed by Accelrys.
  • I-TASSER. Internet service for protein structure and function predictions. Models are built based on multiple-threading alignments by LOMETS and iterative TASSER simulations. I-TASSER (as ‘Zhang-Server’) was ranked as the No 1 server in recent CASP7 and CASP8 experiments. Exists as a standalone package. Provided by the University of Michigan.
  • LOMETS. (Local Meta-Threading-Server). On-line web service for protein structure prediction. It generates 3D models by collecting high-scoring target-to-template alignments from 8 locally-installed threading programs (FUGUE, HHsearch, MUSTER, PPA, PROSPECT2, SAM-T02, SPARKS, SP3). Exists as a standalone package. Provided by the University of Michigan.
  • ProModel. Allows homology modeling from either a selected template or a user defined template. Modeling in manual mode allows mutation, excision, deletion, insertion of residues or insertion of a loop by selecting the start and end anchors. Automated homology modeling can be performed by reading in the template file obtained from a local BLAST. ProModel enables analysis of the target protein structure, active site and channels. Provided by VLife.
  • TASSER-Lite. Protein structure comparative modeling tool. It is limited to protein target-template pairs whose pairwise sequence identity is >25% to the best threading template. It is optimized to model single domain proteins whose lengths range from 41-200 residues. Freely available to all academic users and not-for-profit institutions. Provided by the Skolnick Research Group.
  • SCRWL. Program for prediction of protein sice chains prediction, based on the Dunbrack backbone-dependent rotamer library. Provided by the Dunbrack Lab.
  • Biskit. Free and open source modular, object-oriented Python library for structural bioinformatics research that wraps external programs (BLAST, T-Coffee and Modeller) into an automated workflow. Developed by the institut Pasteur.
  • RaptorX. Protein structure prediction program developed by Xu group, with a particular focus on the alignment of distantly-related proteins with sparse sequence profile and that of a single target to multiple templates. Currently, RaptorX consists of four major modules: single-template threading, alignment quality assessment, multiple-template threading and fragment-free approach to free modeling. Also exists as a web service.
  • Prime. Fully-integrated protein structure prediction program, providing graphical interface, sequence alignment, secondary structure prediction, homology modeling, protein refinement, loop-prediction, and side-chain prediction. Developed by Schrödinger.
  • ProSide. Predicts protein sidechain conformation. Since the residue-substitution by the target amino-acid sequence is possible, ProSide can be used also for simple homology modeling, in case there are neither insertion nor deletion. Can perform global optimization calculation of a complex, by putting ligand to a binding site, and optimizing positions and conformations of ligand and amino-acid sidechains. Distributed by IMMD.
  • CABS. Versatile reduced representation tool for molecular modeling, including: de novo folding of small proteins, comparative modeling (especially in cases of poor templates) and structure prediction based on sparse experimental data. Developed by the Warsaw University.

Web services and databases

  • SWISS-MODEL. Fully automated protein structure homology-modeling server, accessible via the ExPASy web server, or from the program DeepView (Swiss Pdb-Viewer).
  • SWISS-MODEL Repository. Database of annotated three-dimensional comparative protein structure models generated by the fully automated homology-modelling pipeline SWISS-MODEL.
  • Robetta. Web server. Rosetta homology modeling and ab initio fragment assembly with Ginzu domain prediction.
  • I-TASSER. Internet service for protein structure and function predictions. Models are built based on multiple-threading alignments by LOMETS and iterative TASSER simulations. I-TASSER (as ‘Zhang-Server’) was ranked as the No 1 server in recent CASP7 and CASP8 experiments. Exists as a standalone package. Provided by the University of Michigan.
  • RaptorX web server. Protein structure prediction web server developed by Xu group, with a particular focus on the alignment of distantly-related proteins with sparse sequence profile and that of a single target to multiple templates. Currently, RaptorX consists of four major modules: single-template threading, alignment quality assessment, multiple-template threading and fragment-free approach to free modeling. Due to limited computational power, this server offers the first three modules for regular usage. Also exists as a standalone program.
  • TIP database. The Target Informatics Platform (TIP) database contains more than 195,000 high resolution protein structures and homology models, with annotated small molecule binding sites, covering major drug target families including proteases, kinases, phosphatases, phosphodiesterases, nuclear receptors, and GPCRs. The TIP database automatically and self-consistently updates itself, possibly including proprietary sequence and structure data. Developed and maintained by Eidogen-Sertanty, Inc.
  • iProtein. iPad application providing access to the Eidogen-Sertanty’s Target Informatics Platform (TIP).
  • ModBase. Database of three-dimensional protein models calculated by comparative modeling. The models are derived by ModPipe, an automated modeling pipeline relying on the programs PSI-BLAST and MODELLER. The database also includes fold assignments and alignments on which the models were based. MODBASE also contains information about putative ligand binding sites, SNP annotation, and protein-protein interactions.
  • Protinfo ABCM. The Protinfo web server consists of a series of discrete modules that make predictions of, and provide information about, protein folding, structure, function, interaction, evolution, and design by applying computational methodologies developed by the Samudrala Computational Biology Research Group.
  • PMP. (Protein Model Portal). Gives access to various models computed by comparative modeling methods provided by different partner sites, and provides access to various interactive services for model building, and quality assessment. Provided by the Swiss Institute of BioInformatics and the University of Basel.
  • HHpred. Web server for homology detection & structure prediction by HMM-HMM comparison.
  • CPHmodels. Protein homology modeling server. The template recognition is based on profile-profile alignment guided by secondary structure and exposure predictions. Maintained by the Center for Biological Sequence Analysis, Denmmark.
  • GeneSilico Metaserver. Gateway to various methods for protein structure prediction, including primary structure, seconday structure, transmembrane helices, disordered regions, disulfide bonds, nucleic acid binding residues in proteins and tertiary structure. Maintained by the Bujnicki laboratory in IIMCB, Warsaw, Poland.
  • QUARK. Internet service for ab initio protein folding and protein structure prediction, which aims to construct the correct protein 3D model from amino acid sequence only. QUARK models are built from small fragments (1-20 residues long) by replica-exchange Monte Carlo simulation under the guide of an atomic-level knowledge-based force field. QUARK was ranked as the No 1 server in Free-modeling (FM) in CASP9. Since no global template information is used in QUARK simulation, the server is suitable for proteins which are considered without homologous templates. Provided by the University of Michigan.
  • SuperLooper. SuperLooper provides an online interface for the automatic, quick and interactive search and placement of loops in proteins. Loop candidates are selected from a database (LIMP) comprising ~ 180.000 loops of membrane proteins or, alternatively, from (LIP) containing ~ 513.000.00 segments of water-soluble proteins with lengths up to 35 residues. In addition to several filtering criteria regarding structural and sequence features, the software allows for placing the loop within the predicted membrane-water interface. Provided by Charité Berlin, Structural Bioinformatics Group.
  • PEP-FOLD. De novo approach aimed at predicting peptide structures from amino acid sequences. This method, based on structural alphabet SA letters to describe the conformations of four consecutive residues, couples the predicted series of SA letters to a greedy algorithm and a coarse-grained force field. Developed by the University of Paris Diderot.
  • LOMETS. (Local Meta-Threading-Server). On-line web service for protein structure prediction. It generates 3D models by collecting high-scoring target-to-template alignments from 8 locally-installed threading programs (FUGUE, HHsearch, MUSTER, PPA, PROSPECT2, SAM-T02, SPARKS, SP3). Exists as a standalone package. Provided by the University of Michigan.
  • ESyPred3D. Automated homology modeling web server in which lignments are obtained by combining, weighting and screening the results of several multiple alignment programs. The final three dimensional structure is built using the modeling package MODELLER.
  • MolProbity. Web service for all-atom structure validation for macromolecular crystallography. Maintained by the Richardson Lab, Duke University.
  • PSiFR. (Protein Structure and Function predicton Resource) provides integrated tools for protein tertiary structure prediction and structure and sequence-based function annotation. The web portal provides access to TASSER, TASSER-Lite and MetaTASSER and DBD-Hunter, and the enzyme function inference engine EFICAz2.
  • chunk-TASSER. Protein structure prediction method that combines threading templates from SP3 and ab initio folded chunk structures (three consecutive segments of regular secondary structures). For extreme hard targets. This web service is freely available to all academic users and not-for-profit institutions. Provided by the Skolnick. Research Group.
  • MetaTASSER. Protein tertiary prediction method that employs the 3D-Jury approach to select threading templates from SPARKS, SP3 and PROSPECTOR_3, which provides aligned fragments and tertiary restraints as an input to TASSER (Threading/ASSEmbly/Refinement) procedure to generate full-length models. This web service is freely available to all academic users and not-for-profit institutions. Provided by the Skolnick.
  • pro-sp3-TASSER. Protein Structure Prediction tool that uses a single threading method with multiple scoring to identify templates. Short TASSER runs generate full length models that are selected by TASSER-QA and FTCOM ranking procedures. pro-sp3-TASSER performs better than MetaTASSER for medium/hard targets, but is computationally more expensive. This web service is freely available to all academic users and not-for-profit institutions. Provided by the Skolnick.
  • BSR. Binding Site Refinement employs a new template-based method for the local refinement of ligand-binding regions in protein models using closely as well as distantly related templates identified by threading. This web service is freely available to all academic users and not-for-profit institutions. Provided by the Skolnick.
  • 3D-Jigsaw. Automated system to build three-dimensional models for proteins based on homologues of known structure.
  • Geno3D. Automatic modeling of proteins three-dimensional structure using comparative protein structure modelling by spatial restraints (distances and dihedral) satisfaction. Provided by the Pole Bioinformatique Lyonnais.
  • VADAR. (Volume, Area, Dihedral Angle Reporter) is a compilation of more than 15 different algorithms and programs for analyzing and assessing peptide and protein structures from their PDB coordinate data to quantitatively and qualitatively assess protein structures determined by X-ray crystallography, NMR spectroscopy, 3D-threading or homology modelling. Provided by the University of Alberta, Canada.
  • phyre. (Protein Homology/analogY Recognition Engine). Automated 3D model building using profile-profile matching and secondary structure. Provided by the Structural Bioinformatics group, Imperial College London.
  • HMMSTR/Rosetta. Predicts the structure of proteins from the sequence : secondary, local, supersecondary, and tertiary. Provided by the Depts of Biology & Computer Science, Rensselaer Polytechnic Institute
  • GPCRautomodel. Web service that automates the homology modeling of mammalian olfactory receptors (ORs) based on the six three-dimensional (3D) structures of G protein-coupled receptors (GPCRs) available so far and (ii) performs the docking of odorants on these models, using the concept of colony energy to score the complexes. Provided by INRA.
  • FALC-Loop. Web server for protein loop modeling using a fragment assembly and analytical loop closure method.
  • IntFOLD. Web resource for protein fold recognition, 3D model quality assessment, intrinsic disorder prediction, domain prediction and ligand binding site prediction.
  • PEPstr. Web server to predict the tertiary structure of small peptides with sequence length varying between 7 to 25 residues. The prediction strategy is based on the realization that β-turn is an important and consistent feature of small peptides in addition to regular structures. Provided by the Bioinformatics Centre, Institute of Microbial Technology, Chandigarh.
  • FOBIA. Folding by hierarchical assembly. Provided by the structural Bioinformatics group at Tel-Aviv University.

Binding site prediction

MED-SuMo, CAVER, FINDSITE, sc-PDB, CASTp, Pocketome, 3DLigandSite, metaPocket, PocketAnnotate, …

Software

  • MED-SuMo. Program for macromolecules surface similarity detection. Searches into 3D databases, find similar binding surfaces and generate 3D superpositions based on common surface chemical features and similar shape. Can be used for site mining, drug repurposing and site classification at PDB scale. Distributed by MEDIT.
  • CAVER. Software tool for analysis and visualisation of tunnels and channels in protein structures. Provided by the Masaryk University.
  • FINDSITE. Threading-based binding site prediction/protein functional inference/ligand screening algorithm that detects common ligand binding sites in a set of evolutionarily related proteins. Crystal structures as well as protein models can be used as the target structures. Freely available to all academic users and not-for-profit institutions. Provided by the Skolnick Research Group.
  • fpocket. Open source protein pocket (cavity) detection algorithm based on Voronoi tessellation. Developed in the C programming language and currently available as command line driven program. fpocket includes two other programs (dpocket & tpocket) that allow you to extract pocket descriptors and test own scoring functions respectively. Also contains a druggability prediction score.
  • GHECOM. Program for finding multi-scale pockets on protein surfaces using mathematical morphology. Free open source.
  • LIGSITEcsc. Program for the automatic identification of pockets on protein surface using the Connolly surface and the degree of conservation.
  • SURFNET. Generates surfaces and void regions between surfaces from coordinate data supplied in a PDB file.
  • SiteHound. Identifies ligand binding sites by computing interactions between a chemical probe and a protein structure. The input is a PDB file of a protein structure, the output is a list of “interaction energy clusters” corresponding to putative binding sites.
  • ICM-PocketFinder. Binding site predictor based on calculating the drug-binding density field and contouring it at a certain level. Provided by Molsoft.
  • SiteMap. Program for binding site identification. Distributed by Schrodinger.
  • MSPocket. Orientation independent program for the detection and graphical analysis of protein surface pockets. A MSPocket plugin for PyMOL provides a graphical user interface for runing MSPocket and render its results in PyMOL. It is included in the download. Free and open source.
  • POCASA. (POcket-CAvity Search Application). Automatic web service that implements the algorithm named Roll which can predict binding sites by detecting pockets and cavities of proteins of known 3D structure. Maintained by the Hokkaido University.
  • Pfinder. Method for the prediction of phosphate-binding sites in protein structures. provided by the University of Rome.
  • PocketPicker. Pymol plugin for PocketPicker, a program for the analysis of ligand binding-sites with shape descriptors.
  • VOIDOO. Software to find cavities and analyse volumes.
  • FunFOLDQA. Program to assess the quality ligand binding site residue predictions based on 3D models of proteins. Free program written in java. Developped by the University of Reading.
  • McVol. Program to integrate the molecular volume, solven accessible volume an Van der Waals volume of proteins using a Monte carlo algorithm. Based on this calculations, McVol is also able to identify internal cavities as well as surface clefts und fill these cavities with water molecules. Additionally, a membrane of dummy atoms can be placed as a disc atound the protein. The program is available under the Gnu Public Licence.
  • POVME. Free and open source program for measuring binding-pocket volumes. Developed by the National Biomedical Computation Resource.

Databases

  • sc-PDB. Annotated Database of Druggable Binding Sites from the Protein DataBank. Provided by the university of Strasbourg.
  • CASTp. Computed Atlas of Surface Topography of proteins. Provides identification and measurements of surface accessible pockets as well as interior inaccessible cavities, for proteins and other molecules. castP server uses the weighted Delaunay triangulation and the alpha complex for shape measurements.
  • Pocketome. Encyclopedia of conformational ensembles of all druggable binding sites that can be identified experimentally from co-crystal structures in the Protein Data Bank.
  • PocketAnnotate database. Database of non-redundant binding sites created from all the existing protein-ligand complexes from the PDB. Redundancy was reduced by ensuring that the best possible binding site for a given ligand is chosen (by taking into account the highest resolution structure) per fold of a protein. Maintained by the Department of Biochemistry, Indian Institute of Science.
  • KBDOCK. 3D database system that defines and spatially clusters protein binding sites for knowledge-based protein docking. KBDOCK integrates protein domain-domain interaction information from 3DID and sequence alignments from PFAM together with structural information from the PDB in order to analyse the spatial arrangements of DDIs by Pfam family, and to propose structural templates for protein docking. Provided by Inria, Nancy, France.
  • PDBe motifs and Sites. Can be used to examine the characteristics of the binding sites of single proteins or classes of proteins such as Kinases and the conserved structural features of their immediate environments either within the same specie or across different species.
  • LigASite. Dataset of biologically relevant binding sites in protein structures. It consists of proteins with one unbound structure and at least one structure of the protein-ligand complex. Both a redundant and a non-redundant (sequence identity lower than 25%) version is available.
  • PROtein SURFace ExploreR. Contains information about structural similarities with respect to the query surfaces. A pocket search algorithm detected 48,347 potential ligand binding sites from the 9,708 non-redundant protein entries in the PDB database. All-against-all structural comparison was performed for the predicted sites, and the similar sites with the Z-score ≥ 2.5 were selected. These results can be accessed by the PDB code or ligand name.
  • fPOP. Footprinting protein functional surfaces by comparative spatial patterns. Database of the protein functional surfaces identified by shape analysis.
  • SitesBase. Database of known ligand binding sites within the PDB which is navigable by PDB identifier or ligand 3 letter code. Multiple alignments, structural superpositions and links to other structural databases are also available enabling further analysis.
  • PDBSITE. Database on protein active sites and their spatial environment. Provided by GeneNetworks.

Web services

  • 3DLigandSite. Automated method for the prediction of ligand binding sites. Provided by the Imperial London College.
  • metaPocket. Meta server to identify pockets on protein surface to predict ligand-binding sites.
  • PocketAnnotate. Computational pipeline, for facilitating functional annotation of proteins at the level of ligand binding sites. With a structural model as input, PocketAnnotate processes it in three different phases: (a) by identifying ligand binding sites, (b) fast comparison of identified pockets to a database of known ligand-binding sites (c) detailed alignment of high scoring site-pairs. Through these steps, one can obtain clues about possible ligands that can bind to a query protein and hence infer its function. Maintained by the Department of Biochemistry, Indian Institute of Science.
  • DoGSiteScorer. Automated pocket detection and analysis web service which can be used for protein assessment. Predictions with DoGSiteScorer are based on calculated size, shape and chemical features of automatically predicted pockets, incorporated into a support vector machine for druggability estimation. Maintained by the Hamburg University.
  • PocketQuery. Protein-protein interaction (PPI) inhibitor starting points from PPI structure. Quickly identify a small set of residues at a protein interface that are suitable starting points for small-molecule design. Provided by the University of Pittsburgh.
  • PASS. Program for tentative identification of drug interaction pockets from protein structure.
  • DEPTH. Web server to compute depth and predict small-molecule binding cavities in proteins
  • fpocket web server. Open source protein pocket (cavity) detection algorithm based on Voronoi tessellation. Developed in the C programming language and currently available as command line driven program. fpocket includes two other programs (dpocket & tpocket) that allow you to extract pocket descriptors and test own scoring functions respectively. Also contains a druggability prediction score.
  • Active Site Prediction. Web server for computing the cavities in a given protein. Provided by the Supercomputing Facility for Bioinformatics & Computational Biology, IIT Delhi.
  • GHECOM web server. Web server for finding multi-scale pockets on protein surfaces using mathematical morphology.
  • LIGSITEcsc web server. Web server for the automatic identification of pockets on protein surface using the Connolly surface and the degree of conservation.
  • ProBis. Web server for detection of structurally similar binding sites. Maintained by the National Institute of Chemistry, Ljubljana, Slovenia.
  • FunFOLD. Web server to predict likely ligand binding site residues for a submitted amino acid sequence.
  • CAVER. Software tool for analysis and visualisation of tunnels and channels in protein structures. Provided by the Masaryk University.
  • SuMo. Screens the Protein Data Bank (PDB) for finding ligand binding sites matching your protein structure or inversely, for finding protein structures matching a given site in your protein. Provided freely by the Pole Bioinformatique Lyonnais.
  • IBIS. (Inferred Biomolecular Interactions Server). For a given protein sequence or structure query, IBIS reports physical interactions observed in experimentally-determined structures for this protein. IBIS also infers/predicts interacting partners and binding sites by homology, by inspecting the protein complexes formed by close homologs of a given query.
  • FINDSITE. Threading-based binding site prediction/protein functional inference/ligand screening algorithm that detects common ligand binding sites in a set of evolutionarily related proteins. Crystal structures as well as protein models can be used as the target structures. Freely available to all academic users and not-for-profit institutions. Provided by the Skolnick Research Group.
  • PocketDepth. Depth based algortihm for identification of ligand binding sites.
  • Pocket-Finder. Pocket Detection web server based on the Ligsite algorithm.
  • Q-SiteFinder. Web server for ligand binding site prediction
  • Screen2. Tool for identifying protein cavities and computing cavity attributes that can be applied for classification and analysis.
  • SiteHound-web. Identifies ligand binding sites by computing interactions between a chemical probe and a protein structure. The input is a PDB file of a protein structure, the output is a list of “interaction energy clusters” corresponding to putative binding sites. Maintained by the Sanchez lab, at the Mount Sinai School of Medicine, NY, USA.
  • SiteComp. Web server providing three major types of analysis based on molecular interaction fields: binding site comparison, binding site decomposition and multi-probe characterization. Maintained by the Sanchez lab, at the Mount Sinai School of Medicine, NY, USA.
  • ConCavity. Ligand binding site prediction from protein sequence and structure.
  • SplitPocket. Prediction of binding sites for unbound structures.
  • MolAxis. Web server for the identification of channels in macromolecules.
  • PocketPicker web server. Web server for the analysis of ligand binding-sites with shape descriptors.
  • PDBSiteScan. Tool for search for functional sites in protein tertiary structures. Developed in collaboration with Institute of Cytology and Genetics, Novosibirsk.
  • MultiBind. (Multiple Alignment of Protein Binding Sites). Prediction tool for protein binding sites. Users input a set of protein-small molecule complexes and MultiBind predicts the common physio-chemical patterns responsible for protein binding. Exists as a standalone program. Provided by the structural Bioinformatics group at Tel-Aviv University.
  • Docking

Autodock, DOCK, GOLD, SwissDock, DockingServer, 1-Click Docking, COPICAT, …

Software

  • Autodock. Free open source EA based docking software. Flexible ligand. Flexible protein side chains. Maintained by the Molecular Graphics Laboratory, The Scripps Research Institute, la Jolla.
  • DOCK. Anchor-and-Grow based docking program. Free for academic usage. Flexible ligand. Flexible protein. Maintained by the Soichet group at the UCSF.
  • GOLD. GA based docking program. Flexible ligand. Partial flexibility for protein. Product from a collaboration between the university of Sheffield, GlaxoSmithKline plc and CCDC.
  • Glide. Exhaustive search based docking program. Exists in extra precision (XP), standard precision (SP) and virtual High Throughput Screening modes. Ligand and protein flexible. Provided by Schrödinger.
  • GlamDock. Docking program based on a Monte-Carlo with minimization (basin hopping) search in a hybrid interaction matching / internal coordinate search space. Part of the Chil2 suite. Open for general research.
  • GEMDOCK. Generic Evolutionary Method for molecular DOCKing. Program for computing a ligand conformation and orientation relative to the active site of target protein==== Docking – Software ====
  • iGEMDOCK. Graphic environment for the docking, virtual screening, and post-screening analysis. Free for non commercial researches. For Windows and Linux.
  • HomDock. Progam for similarity-based docking, based on a combination of the ligand based GMA molecular alignment tool and the docking tool GlamDock. Part of the Chil2 suite. Open for general research.
  • ICM. Docking program based on pseudo-Brownian sampling and local minimization. Ligand and protein flexible. Provided by MolSoft.
  • FlexX, Flex-Ensemble (FlexE). Incremental build based docking program. Flexible ligand. Protein flexibility through ensemble of protein structure. Provided by BioSolveIT.
  • Fleksy. Program for flexible and induced fit docking using receptor ensemble (constructed using backbone-dependent rotamer library) to describe protein flexibility. Provided by the Centre for Molecular and Biomolecular Informatics, Radboud University Nijmegen.
  • FITTED. (Flexibility Induced Through Targeted Evolutionary Description). Suite of programs to dock flexible ligands into flexible proteins. This software relies on a genetic algorithm to account for flexibility of the two molecules and location of water molecules, and on a novel application of a switching function to retain or displace water molecules and to form potential covalent bonds (covalent docking) with the protein side-chains. Part of the Molecular FORECASTER package and FITTED Suite. Free for an academic site license (excluding cluster).
  • VLifeDock. Multiple approaches for protein – ligand docking. Provides three docking approches: Grid based docking, GA docking and VLife’s own GRIP docking program. Several scoring functions can be used: PLP score, XCscore and Steric + Electrostatic score. Available for Linux and Windows. Provided by VLife.
  • ParaDockS. (Parallel Docking Suite). Free, open source program, for docking small, drug-like molecules to a rigid receptor employing either the knowledge-based potential PMF04 or the empirical energy function p-Score.
  • Molegro Virtual Docker. Protein-ligand docking program with support for displaceable waters, Induced-fit-docking, user-defined constraints, molecular alignment, ligands-based screening, and KNIME workflow integration. Provided by Molegro.
  • eHiTS. Exhaustive search based docking program. Provided by SimBioSys.
  • DAIM-SEED-FFLD. Free open source fragment-based docking suite. The docking is realized in three steps. DAIM (Decomposition And Identification of Molecules) decomposes the molecules into molecular fragments that are docked using SEED (Program for docking libraries of fragments with solvation energy evaluation). Finally, the molecules are reconstructed ”in situ” from the docked fragments using the FFLD program (Program for fragment-based flexible ligand docking). Developed and maintained by the Computational Structural Biology of ETH, Zurich, Switzerland.
  • Autodock Vina. MC based docking software. Free for academic usage. Flexible ligand. Flexible protein side chains. Maintained by the Molecular Graphics Laboratory, The Scripps Research Institute, la Jolla.
  • FlipDock. GA based docking program using FlexTree data structures to represent a protein-ligand complex. Free for academic usage. Flexible ligand. Flexible protein. Developed by the Department of Molecular Biology at the Scripps Research Institute, la Jolla.
  • FRED. FRED performs a systematic, exhaustive, nonstochastic examination of all possible poses within the protein active site, filters for shape complementarity and pharmacophoric features before selecting and optimizing poses using the Chemgauss4 scoring function. Provided by OpenEye scientific software.
  • HYBRID. Docking program similar to FRED, except that it uses the Chemical Gaussian Overlay (CGO) ligand-based scoring function. Provided by OpenEye scientific software.
  • POSIT. Ligand guided pose prediction. POSIT uses bound ligand information to improve pose prediction. Using a combination of several approaches, including structure generation, shape alignment and flexible fitting, it produces a predicted pose whose accuracy depends on similarity measures to known ligand poses. As such, it produces a reliability estimate for each predicted pose. In addition, if provided with a selection of receptors from a crystallographic series, POSIT will automatically determine which receptor is best suited for pose prediction. Provided by OpenEye scientific software.
  • Rosetta Ligand. Monte Carlo minimization procedure in which the rigid body position and orientation of the small molecule and the protein side-chain conformations are optimized simultaneously. Free for academic and non-profit users.
  • Surflex-Dock. Docking program based on an idealized active site ligand (a protomol), used as a target to generate putative poses of molecules or molecular fragments, which are scored using the Hammerhead scoring function. Distributed by Tripos.
  • CDocker. CHARMm based docking program. Random ligand conformations are generated by molecular dynamics and the positions of the ligands are optimized in the binding site using rigid body rotations followed by simulated annealing. Provided by Accelrys.
  • LigandFit. CHARMm based docking program. Ligand conformations generated using Monte-Carlo techniques are initially docked into an active site based on shape, followed by further CHARMm minimization. Provided by Accelrys.
  • MOE. Suite of medicinal chemistry tools like Ligand-Receptor Docking, Protein/Ligand Interaction Diagrams, Contact Statistics, Electrostatic, & Interaction Maps, LigX (Ligand Optimization in Pocket), Ligand & Structure-Based Scaffold Replacement, Multiple Molecule Flexible Alignment, Conformation Generation, Analysis, & Clustering, Active Site Detection & Visualization, Multi-Fragment Search, Ligand & Structure-Based Query Editor, High-Throughput Conformation Generation, Pharmacophore Search. Distributed by Chemical Computing Group.
  • Lead Finder. program for molecular docking, virtual screening and quantitative evaluation of ligand binding and biological activity.Distributed by Moltech. For Windows and linux.
  • YASARA Structure. Adds support for small molecule docking to YASARA View/Model/Dynamics using Autodock and Fleksy. Provided by YASARA.
  • GalaxyDock. Protein-ligand docking program that allows flexibility of pre-selected side-chains of ligand. Developed by the Computational Biology Lab, Department of Chemistry, Seoul National University.
  • MS-Dock. Free multiple conformation generator and rigid docking protocol for multi-step virtual ligand screening.
  • FINDSITE-LHM. Homology modeling approach to flexible ligand docking. It uses a collection of common molecule substructures derived from evolutionarily related templates as the reference compounds in similarity-based ligand binding pose prediction. It also provides a simple scoring function to rank the docked compounds. Freely available to all academic users and not-for-profit institutions. Provided by the Skolnick Research Group.
  • BetaDock. Molecular docking simulation software based on the theory of Beta-complex.
  • ADAM. Automated docking tool. Can be used for vHTS. Distributed by IMMD.
  • hint!. (Hydropathic INTeractions). Estimates LogP for modeled molecules or data files, numerically and graphically evaluates binding of drugs or inhibitors into protein structures and scores DOCK orientations, constructs hydropathic (LOCK and KEY) complementarity maps that can be used to predict a substrate from a known receptor or protein structure or to propose the hydropathic structure from known agonists or antagonists, and evaluates/predicts effects of site-directed mutagenesis on protein structure and stability.
  • DockVision. Docking package including Monte Carlo, Genetic Algorithm, and database screening docking algorithms.
  • PLANTS. (Protein-Ligand ANT System). Docking algorithm based on a class of stochastic optimization algorithms called ant colony optimization (ACO). In the case of protein-ligand docking, an artificial ant colony is employed to find a minimum energy conformation of the ligand in the binding site. These ants are used to mimic the behavior of real ants and mark low energy ligand conformations with pheromone trails. The artificial pheromone trail information is modified in subsequent iterations to generate low energy conformations with a higher probability. Developed by the Konstanz university.
  • EADock. Hybrid evolutionary docking algorithm with two fitness functions, in combination with a sophisticated management of the diversity. EADock is interfaced with the CHARMM package for energy calculations and coordinate handling.
  • EUDOC. Program for identification of drug interaction sites in macromolecules and drug leads from chemical databases.
  • FLOG. Rigid body docking program using databases of pregenerated conformations. Developed by the Merck Research Laboratories.
  • Hammerhead. Automatic, fast fragment-based docking procedure for flexible ligands, with an empirically tuned scoring function and an automatic method for identifying and characterizing the binding site on a protein.
  • ISE-Dock. Docking program which is based on the iterative stochastic elimination (ISE) algorithm.
  • ASEDock. Docking program based on a shape similarity assessment between a concave portion (i.e., concavity) on a protein and the ligand. Developed by yoka Systems.
  • HADDOCK. HADDOCK (High Ambiguity Driven biomolecular DOCKing) is an approach that makes use of biochemical and/or biophysical interaction data such as chemical shift perturbation data resulting from NMR titration experiments, mutagenesis data or bioinformatic predictions. First developed from protein-protein docking, it can also be applied to protein-ligand docking. Developed and maintained by the Bijvoet Center for Biomolecular Research, Netherlands.
  • Computer-Aided Drug-Design Platform using PyMOL. PyMOL plugins providing a graphical user interface incorporating individual academic packages designed for protein preparation (AMBER package and Reduce), molecular mechanics applications (AMBER package), and docking and scoring (AutoDock Vina and SLIDE).
  • Autodock Vina plugin for PyMOL. Allows defining binding sites and export to Autodock and VINA input files, doing receptor and ligand preparation automatically, starting docking runs with Autodock or VINA from within the plugin, viewing grid maps generated by autogrid in PyMOL, handling multiple ligands and set up virtual screenings, and set up docking runs with flexible sidechains.
  • GriDock. Virtual screening front-end for AutoDock 4. GriDock was designed to perform the molecular dockings of a large number of ligands stored in a single database (SDF or Zip format) in the lowest possible time. It take the full advantage of all local and remote CPUs through the MPICH2 technology, balancing the computational load between processors/grid nodes. Provided by the Drug Design Laboratory of the University of Milano.
  • DockoMatic. GUI application that is intended to ease and automate the creation and management of AutoDock jobs for high throughput screening of ligand/receptor interactions.
  • BDT. Graphic front-end application which control the conditions of AutoGrid and AutoDock runs. Maintained by the Universitat Rovira i Virgili,

Web services

  • SwissDock. SwissDock, a web service to predict the molecular interactions that may occur between a target protein and a small molecule.
  • DockingServer. DockingServer offers a web-based, easy to use interface that handles all aspects of molecular docking from ligand and protein set-up.
  • 1-Click Docking. Free online molecular docking solution. Solutions can be visualized online in 3D using the WebGL/Javascript based molecule viewer of GLmol. Provided by Mcule.
  • Blaster. Public access service for structure-based ligand discovery. Uses DOCK as the docking program and various ZINC Database subsets as the database.Provided by the Shoichet Laboratory in the Department of Pharmaceutical Chemistry at the University of California, San Francisco (UCSF).
  • Mcule docking. Commercial online solution to dock thousands to millions of potential ligands into target structures with the Vina docking tool. Reduced prices for academic. Provided ny Mcule.
  • Docking At UTMB. Web-driven interface for performing structure-based virtual screening with AutoDock Vina. Maintained by the Watowich lab at the University of Texas Medical Branch.
  • Pardock. All-atom energy based Monte Carlo, rigid protein ligand docking, implemented in a fully automated, parallel processing mode which predicts the binding mode of the ligand in receptor target site. Maintained by the Supercomputing Facility for Bioinformatics & Computational Biology, IIT Delhi.
  • FlexPepDock. High-resolution peptide docking (refinement) protocol, implemented within the Rosetta framework. The input for this server is a PDB file of a complex between a protein receptor and an estimated conformation for a peptide.
  • PatchDock. Web server for structure prediction of protein-protein and protein-small molecule complexes based on shape complementarity principles.
  • MEDock. Maximum-Entropy based docking web server for efficient prediction of ligand binding sites.
  • BSP-SLIM. Web service for blind molecular docking method on low-resolution protein structures. The method first identifies putative ligand binding sites by structurally matching the target to the template holo-structures. The ligand-protein docking conformation is then constructed by local shape and chemical feature complementarities between ligand and the negative image of binding pockets. Provided by the University of Michigan.
  • BioDrugScreen. Computational drug design and discovery resource and server. The portal contains the DOPIN (Docked Proteome Interaction Network) database constituted by millions of pre-docked and pre-scored complexes from thousands of targets from the human proteome and thousands of drug-like small molecules from the NCI diversity set and other sources. The portal is also a server that can be used to (i) customize scoring functions and apply them to rank molecules and targets in DOPIN; (ii) dock against pre-processed targets of the PDB; and (iii) search for off-targets. Maintained by the laboratory of Samy Meroueh at the Center for Computational Biology and Bioinformatics at the Indiana University School of Medicine.
  • GPCRautomodel. Web service that automates the homology modeling of mammalian olfactory receptors (ORs) based on the six three-dimensional (3D) structures of G protein-coupled receptors (GPCRs) available so far and (ii) performs the docking of odorants on these models, using the concept of colony energy to score the complexes. Provided by INRA.
  • kinDOCK. Allows comparative docking of ligands into the ATP-binding site of a protein kinase (target). A sequence alignment of the target and a protein kinase profile is performed using HMMER. It uses protein-protein superposition (automatically restricted to the ligand binding pocket) of the target three-dimensional structure with those of known complexes of protein kinases/ligands.
  • iScreen. Web service for docking and screening the small molecular database on traditional Chinese medicine (TCM) on user’s protein. The web-server is implemented with the de novo evolution function for the selected TCM compounds using the LEA3D genetic algorithm.
  • idTarget. Web server for identifying biomolecular targets of small chemical molecules with robust scoring functions and a divide-and-conquer docking approach. Maintained by the National Taiwan University.
  • MetaDock. Online docking solution and docking results analysis service. Docking is done with GNU/GPL-licensed AutoDock v.4 and Dock6 under academic license
  • Score. Allows to calculate some different docking scores of ligand-receptor complex that can be submitted as a whole file containing both interaction partners or as two separated files. The calculation phase is provided by VEGA. Provided by the Drug Design Laboratory of the University of Milano.
  • PLATINUM. Calculates hydrophobic properties of molecules and their match or mismatch in receptor–ligand complexes. These properties may help to analyze results of molecular docking.
  • LPCCSU. Analysis of interatomic Contacts in Ligand-Protein complexes.

Others

  • COPICAT. (COmprehensive Predictor of Interactions between Chemical compounds And Target proteins). System for predicting interactions between chemical compounds and proteins by using Support Vector Machine (SVM). COPICAT realizes comprehensive prediction of protein-chemical interactions by utilizing very general, or the most easily available, data i.e. amino acid sequences and chemical structures. Maintained by the Sakakibara Lab., Dept. Biosciences and Informatics, Keio University.
  • Screening

Pharmer, Catalyst, PharmaGist, Blaster, AnchorQuery, FINDSITECOMB, …

Software

  • Pharmer. Free open source pharmacophore search technology that can search millions of chemical structures in seconds.
  • Catalyst. Pharmacophore Modeling and Analysis; 3D database building and searching; Ligand conformer generation and analysis tools; Geometric, descriptor-based querying; Shape-based screening. Distributed by Accelrys as part of Discovery Studio.
  • PharmaGist. Freely available web server for pharmacophore detection. The download version includes virtual screening capability.
  • LigandScout. Fully integrated platform for virtual screening based on 3D chemical feature pharmacophore models. Developed by inte:ligand.
  • CoLibri. Assembles huge compound collections from multiple sources and various input formats into a virtual screening library, removes duplicates, assesses the distribution of physico-chemical properties of the compounds and makes selections/filter based on any property-threshold, molecules name-pattern or presence/absence of a particular substructure motif. Generates fragments library. Modifies molecules or fragments for generating, transforming and general handling of virtual screening libraries. Distributed by BioSolveIT.
  • Corina. Generates 3D structures for small and medium sized, drug-like molecules. Distributed by Molecular Networks.
  • DecoyFinder. Graphical tool which helps finding sets of decoy molecules for a given group of active ligands. It does so by finding molecules which have a similar number of rotational bonds, hydrogen bond acceptors, hydrogen bond donors, logP value and molecular weight, but are chemically different, which is defined by a maximum Tanimoto value threshold between active ligand and decoy molecule MACCS fingerprints. Optionally, a maximum Tanimoto value threshold can be set between decoys in order to assure chemical diversity in the decoy set.
  • DOVIS. (DOcking-based VIrtual Screening). Tool for virtual screening of chemical databases containing up to millions of small, drug-like compounds. The designed docking-based virtual screening pipeline uses the AutoDock 4.0 program as its docking engine and is integrated into an HPC environment. Its purpose is to remove many technical and administrative complexities involved in employing AutoDock for large scale virtual screening. Developed by the Biotechnology High Performance Computing Software Applications Institute.
  • PyRX. Virtual Screening software for Computational Drug Discovery that can be used to screen libraries of compounds against potential drug targets. PyRx includes docking wizard with easy-to-use user interface which makes it a valuable tool for Computer-Aided Drug Design. PyRx also includes chemical spreadsheet-like functionality and visualization engine that are essential for Rational Drug Design. AutoDock 4 and AutoDock Vina are used as a docking software. Free and open source. For Windows, Linux and Mac OSX.
  • MOLA. Free software for Virtual Screening using AutoDock4/Vina in a computer cluster using non-dedicated multi-platform computers. MOLA is integrated on a customized Live-CD GNU/LINUX operating system and is distributed as a MOLA.iso file. Distributed by BioChemCore.
  • NNScore. Neural-Network-Based Scoring Function for the Characterization of Protein-Ligand Complexes. Reads PDBQT files as input. Developed by the University of California San Diego.
  • WinDock. Program for structure-based drug discovery tasks under a uniform, user friendly graphical interface for Windows-based PCs. Combines existing small molecule searchable three-dimensional (3D) libraries, homology modeling tools, and ligand-protein docking programs in a semi-automatic, interactive manner, which guides the user through the use of each integrated software component. Developed by the Howard University College of Medecine.
  • DockoMatic. GUI application that is intended to ease and automate the creation and management of AutoDock jobs for high throughput screening of ligand/receptor interactions.
  • Screen Suite. Ligand-based screening tool using fingerprints, 2D and 3D descriptors. Distributed by ChemAxon.
  • MolSign. Program for pharmacophore identification and modeling. Can be used for querying databases as a pharmacophore based search. Provided by VLife.
  • eHiTS_LASSO. Similarity searching tool that uses LASSO descriptors (Interacting Surface Point Types) to find molecules with diverse chemical scaffolds but similar surface properties. Distributed by SimBioSys.
  • Spectrophores. Converts three-dimensional molecular property data (electrostatic potentials, molecular shape, lipophilicity, hardness and softness potentials) into one-dimensional spectra independent of the position and orientation of the molecule. It can be used to search for similar molecules and screen databases of small molecules. Open source software developed by Silicos.
  • Shape-it. free open source shape-based alignment tool by representing molecules as a set of atomic Gaussians. Open source software developed by Silicos.
  • Align-it. (Formerly Pharao). Pharmacophore-based tool to align small molecules. The tool is based on the concept of modeling pharmacophoric features by Gaussian 3D volumes instead of the more common point or sphere representations. The smooth nature of these continuous functions has a beneficent effect on the optimisation problem introduced during alignment. Open source software developed by Silicos.
  • Open3DALIGN. Command-line tool aimed at unsupervised molecular alignment. Alignments are computed in an atom-based fashion (by means of a novel algorithm inspired to the LAMDA algorithm by Richmond and co-workers), in a pharmacophore-based fashion using Pharao as the alignment engine, or finally using a combination of the latter two methods. Free open source software. For Windows, Linux and Mac.
  • Molegro Virtual Docker. The built-in Docking Template tool makes it possible to perform ligand-based screening by flexibly aligning a number of ligands (and determine a score for their similarity) and to perform hybrid docking by guiding the docking simulation by combining the template similarity score with a receptor-based docking scoring function. Distributed by Molegro.
  • GMA (Graph based Molecular Alignment). Combined 2D/3D approach for the fast superposition of flexible chemical structures. Part of the Chil2 suite. Open for general research.
  • Fuzzee. Allows the identification of functionally similar molecules, based upon functional and structural groups or fragments. Part of the Chil2 suite. Open for general research.
  • REDUCE. (Formerly FILTER). Tool to filter compounds from libraries using descriptors and functional groups. Part of the Molecular FORECASTER package, from Molecular Forecaster Inc.
  • SELECT. (Selection and Extraction of Libraries Employing Clustering Techniques). Creates subset of libraries by diversity or similarity using clustering techniques. Part of the Molecular FORECASTER package.
  • AutoclickChem. Computer program capable of performing click-chemistry reactions in silico. AutoClickChem can be used to produce large combinatorial libraries of compounds for use in virtual screens. As the compounds of these libraries are constructed according to the reactions of click chemistry, they can be easily synthesized for subsequent testing in biochemical assays. Exists as a web server. Distributed by the National Biomedical Computation Resource.
  • REACTOR. (Rapid Enumeration by Automated Combinatorial Tool and Organic Reactions). Creates library of molecules by combining fragment libraries from a defined reaction, or from a generic attachment point on the fragments. Part of the Molecular FORECASTER package.
  • QUASI. Generates pharmacophores and performs pharmacophore-based virtual screening. Distributed by De Novo Pharmaceuticals.
  • GASP. Genetic Algorithm Similarity Program. Generates pharmacophores using a genetic algorithm. Distributed by Tripos.
  • Tuplets. Pharmacophore-based virtual screening. Distributed by Tripos.
  • KeyRecep. Estimates the characteristics of the binding site of the target protein by superposing multiple active compounds in 3D space so that the physicochemical properties of the compounds match maximally with each other. Can be used to estimate activities and vHTS. Distributed by IMMD.
  • CATS. Chemically Advanced Template Search. Topological pharmacophore descriptor for scaffold-hopping, screening compound selection and focused library profiling. Developed by the Swiss Federal Institute of Technology Zurich (ETHZ).
  • LigPrep. 2D to 3D structure conversions, including tautomeric, stereochemical, and ionization variations, as well as energy minimization and flexible filters to generate ligand libraries that are optimized for further computational analyses. Distributed by Schrodinger.
  • Balloon. Free command-line program that creates 3D atomic coordinates from molecular connectivity via distance geometry and confomer ensembles using a multi-objective genetic algorithm. The input can be SMILES, SDF or MOL2 format. Output is SDF or MOL2.
  • Epik. Enumerates ligand protonation states and tautomers in biological conditions. Distributed by Schrodinger.
  • Bluto. Performs energy minimization and energy analysis of protein or protein-ligand complexes by using force field, for structural optimization of docking models of multiple ligands onto a protein. Provides tabular reports of the energy analysis such as the interaction energy. Suitable for vHTS. Distributed by IMMD.
  • VSDMIP. Virtual Screening Data Management on an Integrated Platform. Comes with a PyMOL graphical user interface. Developed by the Centro de Biología Molecular Severo Ochoa.

Web services

  • Blaster. Public access service for structure-based ligand discovery. Uses DOCK as the docking program and various ZINC Database subsets as the database.Provided by the Shoichet Laboratory in the Department of Pharmaceutical Chemistry at the University of California, San Francisco (UCSF).
  • AnchorQuery. Specialized pharmacophore search for targeting protein-protein interactions. Interactively search more than 20 million readily synthesizable compounds all of which contain an analog of a specific amino acid. Provided by the University of Pittsburgh.
  • FINDSITECOMB. Web service for large scale virtual ligand screening using a threading/structure-based FINDSITE-based approach. It offers the advantage that comparable results are obtained when predicted or experimental structures are used. The user can either provide a protein structure in PDB format or a protein sequence whose structure will first be predicted prior its use in virtual ligand screening. Freely available to all academic users and not-for-profit institutions. Provided by the Skolnick Research Group.
  • FINDSITE-LHM. Homology modeling approach to flexible ligand docking. It uses a collection of common molecule substructures derived from evolutionarily related templates as the reference compounds in similarity-based ligand binding pose prediction. It also provides a simple scoring function to rank the docked compounds. Freely available to all academic users and not-for-profit institutions. Provided by the Skolnick Research Group.
  • New Human GPCR modeling and virtual screening database. Web server to using the new Human GPCR modeling and virtual screening database as well as a new function similarity detection algorithm to screen all human GPCRs against the ZINC8 non-redundant (TC<0.7) ligand set combined with ligands from the GLIDA database (a total of 88,949 compounds). Freely available to all academic users and not-for-profit institutions. Provided by the Skolnick Research Group.
  • e-LEA3D. Searches the FDA approved drugs either by keyword or by substructure. Also builds combinatorial library of molecules.
  • Combinatorial library design. Web server providing a click chemistry engine to connect one or more reactants on a central core (scaffold).
  • eDesign. Web server providing a de novo drug design engine to create new molecules either from scratch (lead-hopping) or based on a user-defined scaffold on which R-groups have to be optimized. Alternatively, the same tool can be used to screen a library of molecules. The sructure-based function is based on the program PLANTS. Maintained by the Institut de Pharmacologie Moléculaire et Cellulaire, France.
  • GFscore. Web server to discriminate true negatives from false negatives in a dataset of diverse chemical compounds using a consensus scoring in a Non-Linear Neural Network manner. The global scoring function is a combination of the five scoring functions found in the Cscore package from Tripos Inc.
  • ZincPharmer. Free online interactive pharmacophore search software for screening the ZINC database. ZINCPharmer can import LigandScout and MOE pharmacophore definitions as well as perform structure-based pharmacophore elucidation.
  • SimDOCK. Allows rapid selection of ligands fitting the active site of the submitted protein by superposition of its three-dimensional structure with those of known complexes of protein/ligands of the family.
  • pep:MMs:MIMIC. Web-oriented tool that, given a peptide three-dimensional structure, is able to automate a multiconformers three-dimensional similarity search among 17 million of conformers calculated from 3.9 million of commercially available chemicals collected in the MMsINC database.
  • wwLig-CSRre. Online Tool to enrich a bank a small compound with compounds similar to a query.
  • Superimposé. Superimposé is a framework for superposition allowing to discover known drug active compounds similar to a given molecule.
  • AURAmol. Web service taking a candidate 2D or 3D molecular shape and use it to search for similarly shaped molecules in large databases. Provided by the University of York.
  • Feature Trees. Web service to perform small molecule similarity searches using the Feature Trees descriptor against a pre-defined set of large compound libraries
  • SiMMap. Web server statistically deriving site-moiety map with several anchors, based on the target structure and several docked compounds. Each anchor includes three elements: a binding pocket with conserved interacting residues, the moiety composition of query compounds and pocket-moiety interaction type (electrostatic, hydrogen bonding or van der Waals). Compound highly agreeing with anchors of site-moiety map are expected to activate or inhibit the target protein.
  • ShaEP. Free program to superimpose two rigid 3D molecular structure models, based on shape and electrostatic potentials, and computes a similarity index for the overlay. It can be used for the virtual screening of libraries of chemical structures against a known active molecule, or as a preparative step for 3D QSAR methods.
  • PharmMapper. Freely accessed web-server designed to identify potential target candidates for the given probe small molecules (drugs, natural products, or other newly discovered compounds with binding targets unidentified) using pharmacophore mapping approach.
  • Target prediction

MolScore-Antivirals, MolScore-Antibiotics, PredictFX, SEA, SuperPred, ReverseScreen3D, …

Software

  • MolScore-Antivirals. Expert system to identify and prioritise antiviral drug candidates. Developed by PharmaInformatic, Germany.
  • MolScore-Antibiotics. Expert system to identify and prioritise antibacterial drug candidates. Developed by PharmaInformatic, Germany.
  • PredictFX. Program to identify and address safety issues. Predicts the profile of affinities against a panel of biological targets, the profile of side effects and the link between side effects and target profile. Distributed by Certera.

Web services

  • SEA. (Similarity ensemble approach) relates proteins based on the set-wise chemical similarity among their ligands. It can be used to rapidly search large compound databases, build cross-target similarity maps and predict possible targets of a small molecule. Provided by the Shoichet Laboratory in the Department of Pharmaceutical Chemistry at the University of California, San Francisco (UCSF).
  • SuperPred. Webservice for drug classification and target prediction. The web-server translates a user-defined molecule into a structural fingerprint that is compared to about 6300 drugs, which are enriched by 7300 links to molecular targets of the drugs, derived through text mining followed by manual curation. Provided by the Institute of Molecular Biology and Bioinformatics, Charité – University Medicine Berlin.
  • ReverseScreen3D. Reverse ligand-based virtual screening tool that searches against a biologically-relevant and automatically-updated subset of ligands extracted from the RCSB Protein Data Bank in order to identify potential target proteins that are likely to bind a given compound. Provided by the University of Leeds.
  • Ligand design

GANDI, LUDI, SPROUT, SwissBioisostere, Glide Fragment Library, e-LEA3D, eDesign, 3DLigandSite, …

Software

  • GANDI. Program for structure-based fragment-based ab initio (de novo) ligand design. Developed and distributed by the Computational Structural Biology group of prof. Amedeo Caflisch, Zurich University.
  • LUDI. Program for automated structure-based drug design, using growing and linking approaches. Distributed by Accelrys as part of Discovery Studio.
  • SPROUT. Program for structure-based fragment-based ab initio ligand design, based on growing and linking approaches. Distributed by SimBioSys.
  • SPROUT-HitOpt. Program for structure-based fragment-based ligand design, based on SPROUT. It is designed to produce structures that are similar to known hit or lead molecules, using core extension and monomer replacement. Distributed by SimBioSys.
  • FlexNovo. Molecular design program based on FlexX that constructs incrementally a ligand in the context of the 3D-structure of the target. Distributed by BioSolveIT.
  • BREED. Program for ligand-based ligand design, by hybridization of known ligands. Distributed by Schrodinger.
  • GeometryFit. Program for structure-based fragment-based ligand design, based on growing and linking approaches. Distributed by GeometryLifeSci.
  • Allegrow. Program for structure-based fragment-based ligand design, based on growing and combinatorial approaches. Distributed by Boston De Novo Design.
  • E-novo. Program for automated structure-based ligand design, using a combinatorial substitution of R-groups on the initial scaffold. Distributed by Accelrys as part of Discovery Studio.
  • BOMB. Program for structure-based fragment-based ligand design, based on a growing approach. Distributed by Cemcomco.
  • EA-Inventor. Program for structure-based fragment-based ligand design, based on a EA approach. Distributed by Tripos.
  • ChIP. Program, based on a genetic algorithm, for the exploration of synthetically feasible small molecule chemical space from commercially available starting materials, directly toward medicinally relevancy, applying predictive computational QSAR models and physicochemical and structural filters. ChIP can take account of propriatary chemical reactions. Developed by Eidogen-Sertanty, Inc.
  • ChemT. Open-source software for building chemical compound libraries, based on a specific chemical template. The compound libraries generated can then be evaluated, using several Virtual Screening tools like molecular docking or QSAR modelling tools. Distributed by BioChemCore.
  • MEGA. Program for structure-based fragment-based ligand design, based on a EA approach. Distributed by Noesis Informatics (NSisToolkit).
  • LigBuilder. Program for structure-based fragment-based ab initio ligand design, based on growing, linking and mutation approaches.
  • TOPAS (now DOGS). Program for ligand-based fragment-based ab initio ligand design, using molecular similarity towards a template compound. Developed by the Swiss Federal Institute of Technology Zurich (ETHZ).
  • LeadGrow. Provides features for focused combinatorial library generation and screening to grow a lead molecule and perform lead optimization. Provides Lipinski screen and activity prediction using pre-generated QSAR models. Provided by VLife.
  • Muse. A molecular invention workflow designed to accelerate the identification and optimization of lead candidates. Uses a ligand-based scoring to generate ideas that optimize the shape and pharmacophoric similarity to a set of lead structures. Formerly EAInventor. Distributed by Tripos.
  • Phase. Program for ligand-based drug design using pharmacophore modeling. Distributed by Schrodinger.
  • CombiGlide. Program for ligand-based drug design using ligand-receptor scoring, combinatorial docking algorithms, and core-hopping technology to design focused libraries and identify new scaffolds. Distributed by Schrodinger.
  • MOE. Suite of medicinal chemistry tools like Ligand-Receptor Docking, Protein/Ligand Interaction Diagrams, Contact Statistics, Electrostatic, & Interaction Maps, LigX (Ligand Optimization in Pocket), Ligand & Structure-Based Scaffold Replacement, Multiple Molecule Flexible Alignment, Conformation Generation, Analysis, & Clustering, Active Site Detection & Visualization, Multi-Fragment Search, Ligand & Structure-Based Query Editor, High-Throughput Conformation Generation, Pharmacophore Search. Distributed by Chemical Computing Group.
  • CoLibri. Assembles huge compound collections from multiple sources and various input formats into a virtual screening library, removes duplicates, assesses the distribution of physico-chemical properties of the compounds and makes selections/filter based on any property-threshold, molecules name-pattern or presence/absence of a particular substructure motif. Generates fragments library. Modifies molecules or fragments for generating, transforming and general handling of virtual screening libraries. Distributed by BioSolveIT.
  • ReCore. Replaces a given pre-defined central unit of a molecule (the core), by searching fragments in a 3D database for the best possible replacement, while keeping the rest of the query compound. Additionally, user-defined “pharmacophore” constraints can be employed to restrict solutions. Distributed by BioSolveIT.
  • LigMerge. Program combining structures of known binders to generate similar but structurally distinct compounds that can be tested for binding. Free and open source. Distributed by the National Biomedical Computation Resource.
  • LEGEND. Program for automated structure-based drug design, using an atom-based growing approach. Provided by IMMD.
  • Autogrow. Ligand design using fragment-based growing, docking, and evolutionary techniques. AutoGrow uses AutoDock as the selection operator. Provided by the McCammon Group, UCSD.
  • CrystalDock. Computer algorithm that aids the computational identification of molecular fragments predicted to bind a receptor pocket of interest. CrystalDock identifies the microenvironments of an active site of interest and then performs a geometric comparison to identify similar microenvironments present in ligand-bound PDB structures. Germane fragments from the crystallographic or NMR ligands are subsequently placed within the novel active site. These positioned fragments can then be linked together to produce ligands that are likely to bind the pocket of interest; alternatively, they can be joined to an inhibitor with a known or suspected binding pose to potentially improve binding affinity. Free and opensource. For Mac OSX, Linux and Windows XP. Developed by the National Biomedical Computation Resource.
  • MED-Ligand. Computational fragment-based drug design protocol. Annotated fragments of PDB ligands (MED-Portions) are positioned with MED-SuMo in 3D in a binding site and hybridised with MED-Ligand. Leads are discovered and optimised by hybridisation of MED-Portion chemical moities. Distributed by MEDIT.
  • MedChem Studio. (Formerly ClassPharmer). Cheminformatics platform supporting lead identification and prioritization, de novo design, scaffold hopping and lead optimization. It is integrated with MedChem Designer and ADMET Predictor. Distributed by Simulation Plus, Inc.
  • SkelGen. Suite of software tools for the analysis of structural information on a protein target and the de novo design of molecules to bind into its active site. Takes account of protein flexibility using the ReFlex algorithm. Distributed by De Novo Pharmaceuticals.
  • RACHEL. (Real-time Automated Combinatorial Heuristic Enhancement of Lead compounds). Structure-based all-purpose ligand refinement software package designed to combinatorially derivatize a lead compound to improve ligand-receptor binding. Developed by Drug Design Methodologies and distributed by Tripos.
  • MCSS. CHARMm-based method for docking and minimizing small ligand fragments within a protein binding site. Distributed by Accelrys.
  • DLD. Automated method for the creation of novel ligands, linking up small functional groups that have been placed in energetically favorable positions in the binding site of a target molecule (See MCSS).
  • LoFT. Tool for focused combinatorial library design using a (ligand-based) weighted multiobjective scoring function based on physicochemical descriptors.
  • ACD/Structure Design Suite. Helps chemists optimize the physicochemical properties of their compounds. The software suggests alternative substituents (at a site/sites on the molecule) to drive the property of choice in the desired direction. Helps adjust aqueous solubility, lipophilicity (logP or logD), or change the ionization profile (pKa) of molecules. Distributed by ACD/Labs.
  • HSITE. Program for automated structure-based drug design, using fitting and clipping of planar skeleton.
  • PRO_LIGAND. Program for automated structure-based drug design, using growing and linking approaches.
  • BUILDER. Program for structure-based ab initio ligand design. Finds molecule templates that bind tightly to ‘hot spots’ in the target receptor, and then generate bridges to join these templates.
  • CONCERTS. Program for structure-based ab initio ligand design. Fragments are move independently about a target active site during a molecular dynamics simulation and are linked together when the geometry between proximal fragments is appropriate.
  • ADAPT. Program for structure-based ab initio ligand design based pn the DOCK docking software.
  • CoG. Program for ligand-based ab initio ligand design, using a graph-based genetic algorithm.
  • Flux. Program for ligand-based ligand design using a EA approach.
  • LCT. Program for structure-based ligand design using a linking approach.
  • Biogenerator. Program for structure-based design of macrolides using a biomimetic synthesis of substitutide macrolides approach.
  • ilib diverse. Program for creating virtual libraries of drug-like organic molecules suitable for rational lead structure discovery. Ligands are designed by combining user-defined fragments according to state-of-the-art chemical knowledge. Generated compounds can be filtered according to a variety of physico-chemical filters. Developed by inte:ligand.
  • CAESA. Computer Assisted Estimation of Synthetic Accessibility is a computer program to automatically rank sets of molecules according to their ease of synthesis. Distributed by SimBioSys.
  • EMIL. (Example Mediated Innovation for Lead evolution). Suggests chemical modifications to hits to turn them into bona fide leads. EMIL searches through its Knowledge Base looking for similar chemistry and how it was optimized for potency and bioavailability (Iientification of bioisosteric/bioanalogous structures, indication of empirical information of the modification, such as change in physicochemical, in vitro and in vivo effects, etc…). Distributed by CompuDrug.
  • Legio. Indigo-based GUI application that exposes the combinatorial chemistry capabilities of Indigo. Free and open source. Distributed by GGA software.

Databases

  • SwissBioisostere. Freely available database containing information on millions of molecular replacements and their performance in biochemical assays. It is meant to provide researchers in drug discovery projects with ideas for bioisosteric modifications of their current lead molecule, and to give access to the details on particular molecular replacements. Users can provide a molecular fragment and get possible replacements, along with the biological assays in which they were observed. Users can also provide a given molecular replacement and get the corresponding information. The data were created through detection of matched molecular pairs and mining bioactivity data in the ChEMBL database. Developed and maintained by Merck Serono and the Swiss Institute of BioInformatics.
  • Glide Fragment Library. Set of 441 unique small fragments (1-7 ionization/tautomer variants; 6-37 atoms; MW range 32-226) derived from molecules in the medicinal chemistry literature. The set includes a total of 667 fragments with accessible low energy ionization and tautomeric states and metal and state penalties for each compound from Epik. These can be used for fragment docking, core hopping, lead optimization, de novo design, etc. Provided by Schrödinger.

Web services

  • e-LEA3D. Invents ideas of ligand (scaffold-hopping) by the de novo drug design program LEA3D.
  • eDesign. Web server providing a de novo drug design engine to create new molecules either from scratch (lead-hopping) or based on a user-defined scaffold on which R-groups have to be optimized. Alternatively, the same tool can be used to screen a library of molecules. The sructure-based function is based on the program PLANTS. Maintained by the Institut de Pharmacologie Moléculaire et Cellulaire, France.
  • 3DLigandSite. Automated method for the prediction of ligand binding sites. Provided by the Imperial London College.
  • PASS. Program for tentative identification of drug interaction pockets from protein structure.
  • DEPTH. Web server to compute depth and predict small-molecule binding cavities in proteins
  • Binding free energy estimation

Hyde, X-score, NNScore, DSXONLINE, BAPPL server, BAPPL-Z server, …

Software

  • Hyde. Entirely new approach to assess binding affinities and contributions to binding of a complex, with a visual feedback at atomic detail. Hyde shows which regions of a complex contribute favorably and infavorably to the binding. Allows modifying a molecule interactively to optimize a complex and trigger new lead optimization ideas. Hyde is entirely based on physics-principles and has not been trained or calibrated on experimental data. Distributed by BioSolveIT.
  • X-score. Program for computing the binding affinities of the given ligand molecules to their target protein. X-Score is released to the public for free.
  • NNScore. Python script for computing binding free energies from PDBQT files of the receptor and the ligand, using a neural network approach. Free and open source. Developed by the McCammon Lab, UCSD.
  • eHITS_Score. The eHiTS Scoring function is based upon the relative geometries of the ligand and receptor surface points. Complementary surface point receive a positive score, and repulsive surface points receive a penalty score. additional terms are used to reflect all the factors affecting binding, including depth, intramolecular interactions, receptor coverage and others.

Web services

  • DSXONLINE. (Formerly DrugScoreONLINE). Web-based user interface for the knowledge-based scoring functions DSX.
  • BAPPL server. Binding Affinity Prediction of Protein-Ligand (BAPPL) server computes the binding free energy of a non-metallo protein-ligand complex using an all atom energy based empirical scoring function.
  • BAPPL-Z server. Binding Affinity Prediction of Protein-Ligand complex containing Zinc [ BAPPL-Z ] server computes the binding free energy of a zinc containing metalloprotein-ligand complex using an all atom energy based empirical scoring function.
  • PreDDICTA. Predict DNA-Drug Interaction strength by Computing ΔTm and Affinity of binding.
  • PharmaGist. Freely available web server for pharmacophore detection. The download version includes virtual screening capability.
  • IC50-to-Ki converter. Computes Ki values from experimentally determined IC50 values for inhibitors of enzymes that obey classic Michaelis-Menten kinetics and of protein-ligand interactions
  • QSAR

cQSAR, clogP, ClogP/CMR, MOLE db, ChemDB/Datasets, Datasets from the Milano Chemometrics and QSAR Research Group, OCHEM, MolInfo, E-Dragon, …

Software

  • cQSAR. A regression program that has dual databases of over 21,000 QSAR models. Distributed by BioByte.
  • clogP. Program for calculating log Poct/water from structure. Distributed by BioByte.
  • ClogP/CMR. Estimates Molar Refractivity and logP. Distributed by Tripos.
  • Topomer CoMFA. 3D QSAR tool that automates the creation of models for predicting the biological activity or properties of compounds. Distributed by Tripos.
  • QSARPro. QSAR software for evaluation of several molecular descriptors along with facility to build the QSAR equation (linear or non-linear regression) and use it for predicting the activities of test/new set of molecules. Performs 2D and 3D QSAR, and provides GQSAR, a group based QSAR approach establishing a correlation of chemical group variation at different molecular sites of interest with the biological activity. Works on LInux and Windows. Provided by VLife.
  • MedChem Studio. (Formerly ClassPharmer). Cheminformatics platform supporting lead identification and prioritization, de novo design, scaffold hopping and lead optimization. It is integrated with MedChem Designer and ADMET Predictor. Distributed by Simulation Plus, Inc.
  • Surflex-Sim. Performs the alignment of molecules by maximizing their three-dimensional similarity. Surflex-Sim uses a surface-based morphological similarity function while minimizing the overall molecular volume of the aligned structures. Distributed by Tripos.
  • QSAR with CoMFA. Builds statistical and graphical models that relate the properties of molecules (including biological activity) to their structures. Several structural descriptors can be calculated, including EVA and the molecular fields of CoMSIA. Distributed by Tripos.
  • Almond. 3D-QSAR approach using GRid-INdependent Descriptors (GRIND). Starting with a set of 3D structures, Almond employs GRID3 force field to generate Molecular Interaction Fields (MIFs). The information in the MIFs is transformed to generate information-rich descriptors independent of the location of the molecules within the grid. Distributed by Tripos.
  • GALAHAD. GA-based program to develop pharmacophore hypotheses and structural alignments from a set of molecules that bind at a common site. No prior knowledge of pharmacophore elements, constraints, or molecular alignment is required. Distributed by Tripos.
  • Molegro Data Modeller. A program for building regression or classification models, performing feature selection and cross-validation, principal component analysis, high-dimensional visualization, clustering, and outlier detection. Provided by Molegro.
  • Hologram QSAR (HQSAR). Program using molecular holograms and PLS to generate fragment-based structure-activity relationships. Unlike other 3D-QSAR methods, HQSAR does not require alignment of molecules.
  • cQSAR. A regression program that has dual databases of over 21,000 QSAR models. Distributed by BioByte.
  • McQSAR. Free program to generates quantitative structure-activity relationships (QSAR equations) using the genetic function approximation paradigm. For Windows and Linux.
  • Open3DQSAR. Program aimed at high-throughput generation and chemometric analysis of molecular interaction fields (MIFs). Free open source software. For Windows, Linux and Mac.
  • PaDEL-Descriptor. Free software to calculate molecular (797) descriptors and (10) fingerprints. Can be used from command lines or GUI. Provided by the National University of Singapore.
  • Codessa. Derives descriptors using quantum mechanical results from AMPAC. These descriptors are then used to develop QSAR/QSPR models.
  • KeyRecep. Estimates the characteristics of the binding site of the target protein by superposing multiple active compounds in 3D space so that the physicochemical properties of the compounds match maximally with each other. Can be used to estimate activities and vHTS. Distributed by IMMD.
  • OpenMolGRID. Uses a Grid approach to deal with large-scale molecular design and engineering problems. The methodology used relies on Quantitative Structure Property/Activity Relationships (QSPR/QSAR).
  • Molconn-Z. Standard program for generation of Molecular Connectivity, Shape, and Information Indices for Quantitative Structure Activity Relationship (QSAR) Analyses.
  • CODESSA Pro. Program for developing quantitative structure-activity/property relationships (QSAR/QSPR. Distributed by CompuDrug.
  • MCASE. Machine learning approach to automatically evaluate compounds/activity data set and identify the structural features responsible for activity (biophores). It then creates organized dictionaries of these biophores and develops ad hoc local QSAR correlations. Distributed by MultiCASE.
  • hint!. (Hydropathic INTeractions). Estimates LogP for modeled molecules or data files, numerically and graphically evaluates binding of drugs or inhibitors into protein structures and scores DOCK orientations, constructs hydropathic (LOCK and KEY) complementarity maps that can be used to predict a substrate from a known receptor or protein structure or to propose the hydropathic structure from known agonists or antagonists, and evaluates/predicts effects of site-directed mutagenesis on protein structure and stability.
  • smirep. System for predicting the structural activity of chemical compounds.

Databases

  • MOLE db. Molecular Descriptors Data Base is a free on-line database comprised of 1124 molecular descriptors calculated for hundreds of thousands of molecules.
  • ChemDB/Datasets. Experimentally annotated subsets of the ChemDB for machine learning and searching experiments.
  • Datasets from the Milano Chemometrics and QSAR Research Group. References Data Sets
  • OCHEM Database. (Online Chemical Modeling Environment project). Online database of experimental measurements integrated with a modeling environment. User can submit experimental data or use the data uploaded by other users to build predictive QSAR models for physical-chemical or biological properties. Provided by eADMET GmbH and the Institute of Bioinformatics & Systems Biology at Helmholtz Zentrum München.

Web services

  • OCHEM. (Online Chemical Modeling Environment project). Online database of experimental measurements integrated with a modeling environment. User can submit experimental data or use the data uploaded by other users to build predictive QSAR models for physical-chemical or biological properties. Provided by eADMET GmbH and the Institute of Bioinformatics & Systems Biology at Helmholtz Zentrum München.
  • MolInfo. Calculate / Predict Molecular Properties.
  • E-Dragon. Online version of DRAGON, which is an application for the calculation of molecular descriptors developed by the Milano Chemometrics and QSAR Research Group. These descriptors can be used to evaluate molecular structure-activity or structure-property relationships, as well as for similarity analysis and highthroughput screening of molecule databases. Provided by the Virtual Computational Chemistry Laboratory.
  • Pattern Match Counter. Counts Functional Groups (sub-structures) in molecules.
  • Pattern Count Screen. Screens by Functional Groups.
  • Partial Least Squares Regression (PLSR). Generates model construction and prediction of activity/property using the Partial Least Squares (PLS) regression technique. Provided by the Virtual Computational Chemistry Laboratory.
  • OSIRIS Property Explorer. Integral part of Actelion’s inhouse substance registration system. Calculates on-the-fly various drug-relevant properties for drawn chemical structures, including cLogP and water solubility.
  • XScore-LogP. Calculates the octanol/water partition coefficient for a drug, based on a feature of the X-Score program.
  • 3-D QSAR. 3-D QSAR MODELS DATABASE for Virtual Screening. users can process their own molecules by drawing or uploading them to the server and selecting the target for the virtual screening and biological activity prediction.
  • MOLFEAT. Web service to compute molecular fingerprints and molecular descriptors of molecules from their 3D structures, and for computing activity of compounds of specific chemical types against selected targets based on published Quantitative Structure-Activity Relationship (QSAR) models. Currently covers 1,114 fingerprints, 3,977 molecular descriptors, and 23 QSAR models for 16 chemical types against 14 targets. Maintained by the University of Singapore.
  • ADME Toxicity

QikProp, VolSurf, MedChem Designer, ALOGPS, OSIRIS Property Explorer, ToxPredict, PACT-F, TOXNET, Leadscope Toxicity Database, …

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