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Allosteric ligands for the pharmacologically dark receptors GPR68 and GPR65

Author

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  • Xi-Ping Huang

    (University of North Carolina at Chapel Hill
    National Institute of Mental Health Psychoactive Drug Screening Program (NIMH PDSP), School of Medicine, 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
    † Present addresses: National Center for Advancing Translational Sciences (NCATs), 9800 Medical Center Drive, Rockville, Maryland 20850, USA (H.Z.); Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7365, USA (X.C.); Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, Colorado 80309, USA (K.A.S.); Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27514, USA (M.S.F.); Touro College of Osteopathic Medicine, 60 Prospect Avenue, Middletown, New York 10940, USA (A.J.); Department of Structural and Chemical Biology, Department of Oncological Sciences, Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA (J.J.).)

  • Xin Chen

    (Center for Integrative Chemical Biology and Drug Discovery (CICBDD), University of North Carolina at Chapel Hill
    Eshelman School of Pharmacy, University of North Carolina at Chapel Hill
    † Present addresses: National Center for Advancing Translational Sciences (NCATs), 9800 Medical Center Drive, Rockville, Maryland 20850, USA (H.Z.); Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7365, USA (X.C.); Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, Colorado 80309, USA (K.A.S.); Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27514, USA (M.S.F.); Touro College of Osteopathic Medicine, 60 Prospect Avenue, Middletown, New York 10940, USA (A.J.); Department of Structural and Chemical Biology, Department of Oncological Sciences, Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA (J.J.).)

  • Sheryl S. Moy

    (University of North Carolina at Chapel Hill)

  • Kara A. Saddoris

    (University of North Carolina at Chapel Hill
    † Present addresses: National Center for Advancing Translational Sciences (NCATs), 9800 Medical Center Drive, Rockville, Maryland 20850, USA (H.Z.); Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7365, USA (X.C.); Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, Colorado 80309, USA (K.A.S.); Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27514, USA (M.S.F.); Touro College of Osteopathic Medicine, 60 Prospect Avenue, Middletown, New York 10940, USA (A.J.); Department of Structural and Chemical Biology, Department of Oncological Sciences, Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA (J.J.).)

  • Viktoriya D. Nikolova

    (University of North Carolina at Chapel Hill)

  • Martilias S. Farrell

    (University of North Carolina at Chapel Hill
    † Present addresses: National Center for Advancing Translational Sciences (NCATs), 9800 Medical Center Drive, Rockville, Maryland 20850, USA (H.Z.); Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7365, USA (X.C.); Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, Colorado 80309, USA (K.A.S.); Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27514, USA (M.S.F.); Touro College of Osteopathic Medicine, 60 Prospect Avenue, Middletown, New York 10940, USA (A.J.); Department of Structural and Chemical Biology, Department of Oncological Sciences, Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA (J.J.).)

  • Sheng Wang

    (University of North Carolina at Chapel Hill)

  • Thomas J. Mangano

    (University of North Carolina at Chapel Hill
    National Institute of Mental Health Psychoactive Drug Screening Program (NIMH PDSP), School of Medicine, 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
    National Institute of Mental Health Psychoactive Drug Screening Program (NIMH PDSP), School of Medicine, University of North Carolina at Chapel Hill
    † Present addresses: National Center for Advancing Translational Sciences (NCATs), 9800 Medical Center Drive, Rockville, Maryland 20850, USA (H.Z.); Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7365, USA (X.C.); Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, Colorado 80309, USA (K.A.S.); Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27514, USA (M.S.F.); Touro College of Osteopathic Medicine, 60 Prospect Avenue, Middletown, New York 10940, USA (A.J.); Department of Structural and Chemical Biology, Department of Oncological Sciences, Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA (J.J.).)

  • 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
    Eshelman School of Pharmacy, University of North Carolina at Chapel Hill
    † Present addresses: National Center for Advancing Translational Sciences (NCATs), 9800 Medical Center Drive, Rockville, Maryland 20850, USA (H.Z.); Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7365, USA (X.C.); Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, Colorado 80309, USA (K.A.S.); Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27514, USA (M.S.F.); Touro College of Osteopathic Medicine, 60 Prospect Avenue, Middletown, New York 10940, USA (A.J.); Department of Structural and Chemical Biology, Department of Oncological Sciences, Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA (J.J.).)

  • 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
    National Institute of Mental Health Psychoactive Drug Screening Program (NIMH PDSP), School of Medicine, University of North Carolina at Chapel Hill
    Eshelman School of Pharmacy, University of North Carolina at Chapel Hill)

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.

Suggested Citation

  • 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. Deshp, 2015. "Allosteric ligands for the pharmacologically dark receptors GPR68 and GPR65," Nature, Nature, vol. 527(7579), pages 477-483, November.
    • Handle: RePEc:nat:nature:v:527:y:2015:i:7579:d:10.1038_nature15699
    DOI: 10.1038/nature15699
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    Cited by:

    1. Elise Dumas & Beatriz Grandal Rejo & Paul Gougis & Sophie Houzard & Judith Abécassis & Floriane Jochum & Benjamin Marande & Annabelle Ballesta & Elaine Nery & Thierry Dubois & Samar Alsafadi & Bernard, 2024. "Concomitant medication, comorbidity and survival in patients with breast cancer," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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