The translational value of ligand-receptor binding kinetics in drug discovery

Abstract

The translation of in vitro potency of a candidate drug, as determined by traditional pharmacology metrics (such as EC₅₀/IC₅₀ and K_D/K_i values), to in vivo efficacy and safety is challenging. Residence time, which represents the duration of drug-target interaction, can be part of a more comprehensive understanding of the dynamic nature of drug-target interactions in vivo, thereby enabling better prediction of drug efficacy and safety. As a consequence, a prolonged residence time may help in achieving sustained pharmacological activity, while transient interactions with shorter residence times may be favourable for targets associated with side effects. Therefore, integration of residence time into the early stages of drug discovery and development has yielded a number of clinical candidates with promising in vivo efficacy and safety profiles. Insights from residence time research thus contribute to the translation of in vitro potency to in vivo efficacy and safety. Further research and advances in measuring and optimizing residence time will bring a much-needed addition to the drug discovery process and the development of safer and more effective drugs. In this review, we summarize recent research progress on residence time, highlighting its importance from a translational perspective.

Keywords: binding kinetics; drug‐target interaction; koff; residence time; translation.