Binding Kinetics and Pathways of Ligands to GPCRs

Abstract

Previously, drugs were developed focusing on target affinity and selectivity. However, it is becoming evident that the drug-target residence time, related to the off-rate, is an important parameter for successful drug development. The residence time influences both the on-rate and overall effectiveness of drugs. Furthermore, ligand binding is now appreciated to be a multistep process because metastable and/or intermediate binding sites in the extracellular region have been identified. In this review, we summarize experimental ligand-binding data for G-protein-coupled receptors (GPCRs), and their binding pathways, analyzed by molecular dynamics (MD). The kinetics of drug binding to GPCRs are complex and depend on several factors, including charge distribution on the receptor surface, ligand-receptor interactions in the binding channel and the binding site, or solvation.

Keywords: GPCR; molecular dynamics; residence time.