Structure-based discovery of potent and selective melatonin receptor agonists
- University of Southern California, United States
- University of North Carolina Chapel Hill, United States
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
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.
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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Structure-based discovery of potent and selective melatonin receptor agonists
eLife 9:e53779.
https://doi.org/10.7554/eLife.53779
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