New Binding Sites, New Opportunities for GPCR Drug Discovery

• Published in: Trends in biochemical sciences (Amsterdam. Regular ed.) Vol. 44; no. 4; pp. 312 - 330
• Main Authors: Chan, H.C. Stephen, Li, Yi, Dahoun, Thamani, Vogel, Horst, Yuan, Shuguang
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.04.2019
• Subjects: binding sites; drug discovery; drug targets; GPCR; protein–ligand interactions; drug targets; binding sites; GPCR; protein–ligand interactions; drug discovery
• ISSN: 0968-0004; 1362-4326
• DOI: 10.1016/j.tibs.2018.11.011

Many central biological events rely on protein–ligand interactions. The identification and characterization of protein-binding sites for ligands are crucial for the understanding of functions of both endogenous ligands and synthetic drug molecules. G protein-coupled receptors (GPCRs) typically detect extracellular signal molecules on the cell surface and transfer these chemical signals across the membrane, inducing downstream cellular responses via G proteins or β-arrestin. GPCRs mediate many central physiological processes, making them important targets for modern drug discovery. Here, we focus on the most recent breakthroughs in finding new binding sites and binding modes of GPCRs and their potentials for the development of new medicines. G protein-coupled receptors (GPCRs) mediate numerous physiological activities in the body. Recently resolved crystal structures reveal an increasing number of allosteric ligands. In this review, we systematically cluster the locations of these binding sites from the extracellular, the transmembrane, to the intracellular regions. We also analyze the protein–ligand interactions between these allosteric ligands and their corresponding GPCRs. Whether the intriguing binding modes of these ligands can be rationalized for designing new drug molecules remains an open question. Allosteric sites offer new opportunities to improve ligand selectivity. However, generalizing the application of allosteric binding can be difficult. Certain binding sites, such as that in the intracellular regions, may overlap with the G protein-binding sites. This might reduce ligand specificity and unexpected side effects in clinical applications. Nevertheless, a number of allosteric ligands bind to the receptor–lipid interface. Despite the shallow topology in such region for successful structure-based drug design, these locations appear to have a pivotal role in receptor activation and should not be neglected. More importantly, designing allosteric ligands that target orthosteric and the D2.50×50 allosteric sites simultaneously is a more robust strategy for applying rational drug design. Yet, we expect more allosteric sites to be discovered to open more options for developing new medicines.