Xiaojing Cong, Jeremie Topin, Jerome Golebiowski

G protein-coupled receptors (GPCRs), especially the class A, are the most heavily investigated drug targets in the pharmaceutical industry. Tremendous efforts have been made by both industry and academia to understand the molecular structure and function of this large family of transmembrane proteins. Our understanding in GPCR activation has evolved from the classical inactive-active two-state model to a complex view of GPCR conformational ensemble associated with multiple interacting partners such as ligands, allosteric modulators, ions and downstream signaling proteins. New drug targets and ligand design strategies are unveiled. Meanwhile, breakthroughs in X-ray crystallography have resulted in high-resolution structures of over 30 GPCRs, providing structural basis for drug design and functional studies. These enabled wide applications of computational approaches in GPCR research have led to several groundbreaking studies in the last few years. While a large fraction of human GPCRs has yet to be crystallized, homology modeling plays a pivotal role in the simulation of these GPCRs. Here, we review the recent updates on class A GPCR structure and function, with a focus on the applications and perspectives of molecular modeling in GPCR ligand design.