The Affinity Advantage

Drug discovery is a complex, multiparameter optimization process. I argue that a greater emphasis on optimizing binding affinity will accelerate drug discovery. Note that "optimizing" is not always synonymous with "maximizing". While affinity is not the only property 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, alongside other properties, should be viewed as a key strategic component throughout the entire discovery process. A checklist of practical suggestions is offered to enable project teams to more readily achieve the benefits of affinity optimization.