Drug–target residence time and its implications for lead optimization

Abstract

Much of drug discovery today is predicated on the concept of selective targeting of particular bioactive macromolecules by low-molecular-mass drugs. The binding of drugs to their macromolecular targets is therefore seen as paramount for pharmacological activity. In vitro assessment of drug–target interactions is classically quantified in terms of binding parameters such as IC₅₀ or K_d. This article presents an alternative perspective on drug optimization in terms of drug–target binary complex residence time, as quantified by the dissociative half-life of the drug–target binary complex. We describe the potential advantages of long residence time in terms of duration of pharmacological effect and target selectivity.