The Affinity Advantage

Drug discovery is a complex, multi-parameter optimization process. I argue that a greater emphasis on optimizing binding affinity will accelerate the development of new medicines. Note that “optimizing” is not always synonymous with “maximizing.” While affinity is certainly not the only thing that matters, the value of optimizing drug – receptor interactions is profound and often underappreciated. Optimizing affinity provides seven distinct benefits: achieving potent tool compounds more quickly; making compounds with increased potency; making more selective compounds; optimizing drug candidates more quickly; encouraging the pursuit of more synthetically challenging compounds; expanding chemical diversity during lead optimization; and minimizing interactions with "avoid-ome” targets that lead to poor ADME and tox properties. Affinity should be viewed as a key strategic component throughout the entire discovery process – balancing the level of on-target engagement appropriate to the specific mechanism being pursued alongside the need for chemical diversity and the proactive de-risking of off-targets including the avoid-ome. A “checklist” of practical suggestions is offered to enable project teams to more fully embrace the challenges of affinity optimization.