Opinion - Drug-target residence time and its implications for lead optimization

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.