In the pursuit of new pharmaceuticals, many medicinal chemists want to start their leg of the drug discovery race with a drug-sized molecule that binds with a tenacious grip—we’re talking nanomolar potency—to its biological target. After all, there are so many molecular traits to optimize, such as reducing a drug lead’s toxicity and increasing its solubility in the body, that beginning with high-binding affinity seems like starting on the right foot. That’s why high-affinity hits are the primary aim of high-throughput screening (HTS), a bread-and-butter starting point for drug lead discovery.
But a growing number of medicinal chemists are leaving the high-affinity paradigm behind. These researchers are sidestepping some of the cherished tenets of HTS in favor of an emerging drug discovery strategy called fragment-based lead discovery (FBLD).