Kinetics Of Ligand Binding And Signaling

Drugs acting at G protein-coupled receptors (GPCRs) are one of the most important classes of therapeutics. Drug binding and signaling at GPCRs are dynamic events that vary dramatically over time. Despite this, until recently the pharmacology of new GPCR ligands has been quantified almost exclusively at a single time point, providing little or no information on the kinetic events comprising the response. It is now, however, becoming more widely appreciated that in order to fully understand and/or predict clinical drug efficacy over time, a much better understanding of its underlying binding and signaling kinetics is required. This chapter introduces some of the potential clinical benefits of optimizing the kinetics of novel GPCR-targeted therapeutics and reviews the experimental approaches currently available to measure ligand-receptor binding kinetics. It also discusses the growing importance of incorporating the temporal aspects of GPCR signaling into the analysis of agonist efficacy and bias, highlighting some of the novel techniques and reagents becoming available to measure cell signaling in real time.