Discovery of new GPCR ligands to illuminate new biology

Abstract

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.

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Figure 1: GPCR drugs as a percentage of all drugs, by decade of introduction.
Figure 2: GPCRs may activate multiple downstream signaling pathways: role of biased signaling.
Figure 3: Multiple allosteric sites for GPCRs.
Figure 4: Physical and docking screens to deorphanize MRGPRX2.
Figure 5: Novel biased agonists for the μ-opioid receptor.

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Acknowledgements

Support was given by NIH grants U01104974, and R35GM122481, and the NIMH-PDSP. We thank T. Kenakin for discussions of allostery, J. Pottel and A. Levit for reading this manuscript, and the latter for chemoinformatic assistance.

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Correspondence to Bryan L Roth or Brian K Shoichet.

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B.K.S. and B.L.R. are co-founders of Epiodyne, a GPCR ligand discovery company. B.K.S. and J.J.I. are co-founders of Blue Dolphin, a library docking CRO.

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Roth, B., Irwin, J. & Shoichet, B. Discovery of new GPCR ligands to illuminate new biology. Nat Chem Biol 13, 1143–1151 (2017). https://doi.org/10.1038/nchembio.2490

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