1. Biochemistry and Chemical Biology
  2. Computational and Systems Biology
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Structure-based discovery of potent and selective melatonin receptor agonists

  1. Nilkanth Patel
  2. Xi Ping Huang
  3. Jessica Grandner
  4. Linda C Johansson
  5. Benjamin Stauch
  6. John D McCorvy
  7. Yongfeng Liu
  8. Bryan Roth
  9. Vsevolod Katritch  Is a corresponding author
  1. University of Southern California, United States
  2. University of North Carolina Chapel Hill, United States
Research Article
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Cite this article as: eLife 2020;9:e53779 doi: 10.7554/eLife.53779

Abstract

Melatonin receptors MT1 and MT2 are involved in synchronizing circadian rhythms and are important targets for treating sleep and mood disorders, type-2 diabetes and cancer. Here, we performed large scale structure-based virtual screening for new ligand chemotypes using recently solved high-resolution 3D crystal structures of agonist-bound MT receptors. Experimental testing of 62 screening candidates yielded the discovery of 10 new agonist chemotypes with sub-micromolar potency at MT receptors, with compound 21 reaching EC50 of 0.36 nM. Six of these molecules displayed selectivity for MT2 over MT1. Moreover, two most potent agonists, including 21 and a close derivative of melatonin 28, had dramatically reduced arrestin recruitment at MT2, while compound 37 was devoid of Gi signaling at MT1, implying biased signaling. This study validates the suitability of the agonist-bound orthosteric pocket in the MT receptor structures for the structure-based discovery of selective agonists.

Data availability

All chemical structures of candidate hits and chemical quality control information is deposited as Supplementary InformationAll data generated and analysed during this study is included in the main manuscript or supplementary files.

Article and author information

Author details

  1. Nilkanth Patel

    Department of Biological Sciences, University of Southern California, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Xi Ping Huang

    Department of Pharmacology, University of North Carolina Chapel Hill, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2585-653X
  3. Jessica Grandner

    Department of Biological Sciences, University of Southern California, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Linda C Johansson

    Department of Chemistry, University of Southern California, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4776-5142
  5. Benjamin Stauch

    Bridge Institute, University of Southern California, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7626-2021
  6. John D McCorvy

    Department of Pharmacology, University of North Carolina Chapel Hill, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Yongfeng Liu

    Department of Pharmacology, University of North Carolina Chapel Hill, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Bryan Roth

    Department of Pharmacology, University of North Carolina Chapel Hill, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Vsevolod Katritch

    Department of Biological Sciences, University of Southern California, Los Angeles, United States
    For correspondence
    katritch@usc.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3883-4505

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (U24DK116195)

  • Bryan Roth

National Institute of Mental Health (RO1MH112205)

  • Bryan Roth

BioXFEL Science and Technology Center (1231306)

  • Benjamin Stauch

Swedish Research Council (LT000046/2014-L)

  • Linda C Johansson

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Nir Ben-Tal, Tel Aviv University, Israel

Publication history

  1. Received: November 20, 2019
  2. Accepted: February 26, 2020
  3. Accepted Manuscript published: March 2, 2020 (version 1)
  4. Version of Record published: March 18, 2020 (version 2)

Copyright

© 2020, Patel et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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