2. Academic Validation
  3. Allosteric ligands for the pharmacologically dark receptors GPR68 and GPR65

Allosteric ligands for the pharmacologically dark receptors GPR68 and GPR65

  • Nature. 2015 Nov 26;527(7579):477-83. doi: 10.1038/nature15699.
Xi-Ping Huang 1 2,  Joel Karpiak 3,  Wesley K Kroeze 1,  Hu Zhu 1,  Xin Chen 4 5,  Sheryl S Moy 6,  Kara A Saddoris 6,  Viktoriya D Nikolova 6,  Martilias S Farrell 1,  Sheng Wang 1,  Thomas J Mangano 1 2,  Deepak A Deshpande 7,  Alice Jiang 1 2,  Raymond B Penn 7,  Jian Jin 4 5,  Beverly H Koller 8,  Terry Kenakin 1,  Brian K Shoichet 3,  Bryan L Roth 1 2 5
Affiliations

Affiliations

  • 1 Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599-7365, USA.
  • 2 National Institute of Mental Health Psychoactive Drug Screening Program (NIMH PDSP), School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7365, USA.
  • 3 Department of Pharmaceutical Chemistry, University of California at San Francisco, Byers Hall, 1700 4th Street, San Francisco, California 94158-2550, USA.
  • 4 Center for Integrative Chemical Biology and Drug Discovery (CICBDD), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7363, USA.
  • 5 Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7360, USA.
  • 6 Department of Psychiatry and Carolina Institute for Developmental Disabilities (CIDD), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7146, USA.
  • 7 Center for Translational Medicine and Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
  • 8 Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7264, USA.
PMID: 26550826 DOI: 10.1038/nature15699
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.

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