G protein-coupled receptors (GPCRs) mediate a wide range of signalling processes and are targeted by one third of the drugs in clinical use 1. Although most GPCR-targeting therapeutics are small molecules 2 , the endogenous ligands for many GPCRs are peptides (comprising 50 or fewer amino acids), which suggests that this class of molecule could be therapeutically useful. GPCRs are divided into families based on structural similarities. The largest group is the class A (rhodopsinlike) family, followed by the class B (secretin) family. Although other families exist, including class C and the frizzled and adhesion classes, therapeutics have predominantly targeted class A and B GPCRs, so this Review is focused on these two groups. The International Union of Basic and Clinical Pharmacology (IUPHAR) Guide to Pharmacology 3 currently lists 197 class A receptors with known ligands (excluding olfactory, vision, taste and vomeronasal sensory receptors), where 64 (32%) of these bind to endogenous peptides 3. In GPCR class B, there are 20 receptors activated by 15 endogenous peptides. These GPCRs are grouped in the following families, based on the ligand to which they bind: calcitonin, corticotropin-releasing factor, glucagon, parathyroid hormone (which is generally considered to be a peptide, despite its 84-amino-acid length), vasoactive intestinal peptide (VIP) or pituitary adenylate cyclase-activating peptide (PACAP).
G protein-coupled receptors (GPCRs) constitute the largest family of membrane proteins in the human genome and are important therapeutic targets. During the last decade, the number of atomic-resolution structures of GPCRs has increased rapidly, providing insights into drug binding at the molecular level. These breakthroughs have created excitement regarding the potential of using structural information in ligand design and initiated a new era of rational drug discovery for GPCRs. The molecular docking method is now widely applied to model the threedimensional structures of GPCR-ligand complexes and screen for chemical probes in large compound libraries. In this review article, we first summarize the current structural coverage of the GPCR superfamily and the understanding of receptor-ligand interactions at atomic resolution. We then present the general workflow of structure-based virtual screening and strategies to discover GPCR ligands in chemical libraries. We assess the state of the art of this research field by summarizing prospective applications of virtual screening based on experimental structures. Strategies to identify compounds with specific efficacy and selectivity profiles are discussed, illustrating the opportunities and limitations of the molecular docking method. Our overview shows that structure-based virtual screening can discover novel leads and will be essential in pursuing the next generation of GPCR drugs.Significance Statement--Extraordinary advances in the structural biology of G protein-coupled receptors have revealed the molecular details of ligand recognition by this large family of therapeutic targets, providing novel avenues for rational drug design. Structure-based docking is an efficient computational approach to identify novel chemical probes from large compound libraries, which has the potential to accelerate the development of drug candidates.
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