Current and Future Challenges in GPCR Drug Discovery.

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GPCRs play a pervasive physiological role and, in turn, are the leading target class for pharmaceuticals. Beginning with the determination of the structure of rhodopsin, and dramatically accelerating since the reporting of the first ligand-mediated GPCR X-ray structures, our understanding of the structural and functional characteristics of these proteins has grown dramatically. Deploying this now rapidly emerging information for drug discovery has already been extensively demonstrated through a watershed of studies appearing in numerous scientific reports. Included in these expositions are areas such as sites and characteristics of ligand to GPCR binding, protein activation, effector bias, allosteric mechanisms, dimerization, polypharmacology and others. Computational chemistry studies are demonstrating an increasing role in capitalizing on the structural studies to further advance our understanding of these proteins as well as to drive drug discovery. Such drug discovery activities range from the design of orthosteric site inhibitors through, for example, allosteric modulators, biased ligands, partial agonists and bitopic ligands. Herein, these topics are outlined through specific examples in the hopes of providing a glimpse of the state of the field.