GPCR Allosteric Modulator Discovery.

G protein-coupled receptors (GPCRs) influence virtually every aspect of human physiology; about one-third of all marketed drugs target members of this family. GPCR allosteric ligands hold the promise of improved subtype selectivity, spatiotemporal sensitivity, and possible biased property over typical orthosteric ligands. However, only a small number of GPCR allosteric ligands have been approved as drugs or in clinical trials since the discovery process is very challenging. The rapid development of GPCR structural biology leads to the discovery of several allosteric sites and sheds light on understanding the mechanism of GPCR allosteric ligands, which is critical for discovering novel therapeutics. This book chapter summarized different GPCR allosteric modulating mechanisms and discussed validated mechanisms based on allosteric modulator-GPCR complex structures.