Association Rate Constant: The Unsung Hero of Drug Discovery Kinetics

Speakers

Abstract

While the importance of ligand-receptor binding kinetics on drug action is becoming well established, focus to date has been almost entirely on the role of the dissociation constant on drug efficacy and duration of action. The association rate constant, in contrast, has been largely overlooked, with many investigators still considering it diffusion-limited and equivalent across a compound series. This GEN webinar aims to remedy that by turning the spotlight onto the undervalued and oft-ignored association rate constant.

Consideration will first be given to methodological approaches for measuring association rates, with a particular focus on homogeneous time-resolved fluorescence (HTRF^®), as a highly sensitive technology for quantifying binding at membrane receptors. The introduction of such assays has enabled the investigation of many more compounds than previously possible, revealing a surprising dependence of compound affinity on the association rate constant. The discussion will then turn to the potential clinical benefits of optimizing the association rate of new therapeutics. Recent pharmacokinetic/pharmacodynamic modeling studies have revealed an essential role of the association constant in both onset of drug action and magnitude of target occupancy. Finally, it will be argued that optimizing association and dissociation rate kinetics in tandem will yield safer and more efficacious therapeutics.