Binding kinetics of ligands acting at GPCRs

The influence of drug-receptor binding kinetics has often been overlooked during the development of new therapeutics that target G protein-coupled receptors (GPCRs). Over the last decade there has been a growing understanding that an in-depth knowledge of binding kinetics at GPCRs is required to successfully target this class of proteins. Ligand binding to a GPCR is often not a simple single step process with ligand freely diffusing in solution. This review will discuss the experiments and equations that are commonly used to measure binding kinetics and how factors such as allosteric regulation, rebinding and ligand interaction with the plasma membrane may influence these measurements. We will then consider the molecular characteristics of a ligand and if these can be linked to association and dissociation rates.
Highlights • Ligand binding kinetics can be measured using a variety of methods. • Kinetics can be influenced by the local environment surrounding the receptor. • The molecular determinants of kinetics rates are beginning to be understood. • Both kon and koff should be considered during drug discovery.