Discovery of new GPCR ligands to illuminate new biology

• Published in: Nature chemical biology Vol. 13; no. 11; pp. 1143 - 1151
• Main Authors: Roth, Bryan L, Irwin, John J, Shoichet, Brian K
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.11.2017; Nature Publishing Group
• Subjects: 49/47; 631/154/436; 631/92/606; 631/92/613; 96/98; Allosteric properties; Allosteric Regulation; Allosteric Site; Biochemical Engineering; Biochemistry; Biological effects; Biology; Bioorganic Chemistry; Cell Biology; Chemistry; Chemistry/Food Science; Crystal structure; Drug Design; Drug Discovery; G protein-coupled receptors; Humans; Ligands; Molecular Docking Simulation; Neurons; perspective; Pharmacology; Proteins; Reagents; Receptors; Receptors, G-Protein-Coupled - chemistry; Receptors, G-Protein-Coupled - metabolism; Signal Transduction; Signaling
• ISSN: 1552-4450; 1552-4469
• DOI: 10.1038/nchembio.2490

Structure-based computational methods have contributed to recent successes in the development of small molecules to study GPCR function and to act as therapeutics, including the identification of new ligands for orphan GPCRs, allosteric regulators, and biased ligands. Although a plurality of drugs target G-protein-coupled receptors (GPCRs), most have emerged from classical medicinal chemistry and pharmacology programs and resemble one another structurally and functionally. Though effective, these drugs are often promiscuous. With the realization that GPCRs signal via multiple pathways, and with the emergence of crystal structures for this family of proteins, there is an opportunity to target GPCRs with new chemotypes and confer new signaling modalities. We consider structure-based and physical screening methods that have led to the discovery of new reagents, focusing particularly on the former. We illustrate their use against previously untargeted or orphan GPCRs, against allosteric sites, and against classical orthosteric sites that selectively activate one downstream pathway over others. The ligands that emerge are often chemically novel, which can lead to new biological effects.