Structure-based discovery of potent and selective melatonin receptor agonists

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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 G_i 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.

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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.

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Nilkanth Patel

Department of Biological Sciences, University of Southern California, Los Angeles, United States

Competing interests
The authors declare that no competing interests exist.
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.

"This ORCID iD identifies the author of this article:" 0000-0002-2585-653X
Jessica Grandner

Department of Biological Sciences, University of Southern California, Los Angeles, United States

Competing interests
The authors declare that no competing interests exist.
Linda C Johansson

Department of Chemistry, University of Southern California, Los Angeles, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-4776-5142
Benjamin Stauch

Bridge Institute, University of Southern California, Los Angeles, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-7626-2021
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.
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.
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.
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.

"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.

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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.