Understanding drug-target residence time and the implications on drug discovery

INTRODUCTION: High failure rates in clinical drug development are often attributed to inadequate therapeutic efficacy. While binding affinity has traditionally guided lead optimization, it reflects only the equilibrium state of drug-target interactions and often correlates poorly with in vivo pharmacological responses. This limitation has prompted growing interest in kinetic parameters that more accurately capture the dynamic nature of drug-target interactions. AREAS COVERED: ), which has emerged as a crucial determinant of drug efficacy. The authors discuss the impact of residence time on pharmacological outcomes, summarize factors influencing residence time, and outline experimental and computational approaches for its evaluation. This review is based on literature searches conducted using PubMed and Web of Science to identify articles published between the 2000 to 2025. EXPERT OPINION: Integrating residence time and traditional binding affinity provides a more comprehensive framework for understanding drug-target interactions and guiding rational drug design. Optimizing residence time can enhance pharmacodynamic efficacy, improve target selectivity, and enhance safety. Accordingly, residence time is emerging as a key kinetic parameter in modern drug discovery.