Allosteric ligands for the pharmacologically dark receptors GPR68 and GPR65

Xi-Ping Huang, Joel Karpiak, Wesley K. Kroeze, Hu Zhu, Xin Chen, Sheryl S. Moy, Kara A. Saddoris, Viktoriya D. Nikolova, Martilias S. Farrell, Sheng Wang, Thomas J. Mangano, Deepak A. Deshpande, Alice Jiang, Raymond B. Penn, Jian Jin, Beverly H. Koller, Terry Kenakin, Brian K. Shoichet () and Bryan L. Roth ()
Additional contact information
Xi-Ping Huang: University of North Carolina at Chapel Hill
Joel Karpiak: University of California at San Francisco, Byers Hall
Wesley K. Kroeze: University of North Carolina at Chapel Hill
Hu Zhu: University of North Carolina at Chapel Hill
Xin Chen: Center for Integrative Chemical Biology and Drug Discovery (CICBDD), University of North Carolina at Chapel Hill
Sheryl S. Moy: University of North Carolina at Chapel Hill
Kara A. Saddoris: University of North Carolina at Chapel Hill
Viktoriya D. Nikolova: University of North Carolina at Chapel Hill
Martilias S. Farrell: University of North Carolina at Chapel Hill
Sheng Wang: University of North Carolina at Chapel Hill
Thomas J. Mangano: University of North Carolina at Chapel Hill
Deepak A. Deshpande: Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Alice Jiang: University of North Carolina at Chapel Hill
Raymond B. Penn: Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Jian Jin: Center for Integrative Chemical Biology and Drug Discovery (CICBDD), University of North Carolina at Chapel Hill
Beverly H. Koller: School of Medicine, University of North Carolina at Chapel Hill
Terry Kenakin: University of North Carolina at Chapel Hill
Brian K. Shoichet: University of California at San Francisco, Byers Hall
Bryan L. Roth: University of North Carolina at Chapel Hill

Nature, 2015, vol. 527, issue 7579, 477-483

Abstract: Abstract At least 120 non-olfactory G-protein-coupled receptors in the human genome are ‘orphans’ for which endogenous ligands are unknown, and many have no selective ligands, hindering the determination of their biological functions and clinical relevance. Among these is GPR68, a proton receptor that lacks small molecule modulators for probing its biology. Using yeast-based screens against GPR68, here we identify the benzodiazepine drug lorazepam as a non-selective GPR68 positive allosteric modulator. More than 3,000 GPR68 homology models were refined to recognize lorazepam in a putative allosteric site. Docking 3.1 million molecules predicted new GPR68 modulators, many of which were confirmed in functional assays. One potent GPR68 modulator, ogerin, suppressed recall in fear conditioning in wild-type but not in GPR68-knockout mice. The same approach led to the discovery of allosteric agonists and negative allosteric modulators for GPR65. Combining physical and structure-based screening may be broadly useful for ligand discovery for understudied and orphan GPCRs.

Date: 2015
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DOI: 10.1038/nature15699

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