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Nature. 2020 Feb 10. doi: 10.1038/s41586-020-2027-0. [Epub ahead of print]

Virtual discovery of melatonin receptor ligands to modulate circadian rhythms.

Author information

1
Department of Pharmaceutical Chemistry, University of California, San Francisco, California, 94158, USA.
2
Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, 27599-7365, USA.
3
Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, 53226, USA.
4
Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo (SUNY), Buffalo, New York, 14203, USA.
5
Designer Drug Research Unit, National Institute on Drug Abuse Intramural Research Program, Baltimore, Maryland, 21224, USA.
6
Enamine Ltd, Chervonotkatska Street78, Kyiv, 02094, Ukraine.
7
National Taras Shevchenko University of Kyiv, Volodymyrska Street 60, Kyiv, 01601, Ukraine.
8
Chemspace, 7 Deer Park Drive, Suite M-5, Monmouth Junction, NJ, 08852, USA.
9
Bridge Institute, USC Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, California, 90089, USA.
10
Department of Chemistry, University of Southern California, Los Angeles, California, 90089, USA.
11
Department of Pharmaceutical Chemistry, University of California, San Francisco, California, 94158, USA. bshoichet@gmail.com.
12
Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, 27599-7365, USA. bryan_roth@med.unc.edu.
13
Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo (SUNY), Buffalo, New York, 14203, USA. mdubo@buffalo.edu.

Abstract

The neuromodulator melatonin synchronizes circadian rhythms and related physiological functions via actions at two G protein-coupled receptors: MT1 and MT2. Circadian release of high nighttime levels of melatonin from the pineal gland activates melatonin receptors in the suprachiasmatic nucleus of the hypothalamus, synchronizing physiology and behavior to the light-dark cycle1-4. The two receptors are established drug targets for aligning circadian phase in disorders of sleep5,6 and depression7,1-4,8,9. Despite their importance, few if any in vivo active MT1 selective ligands have been reported2,8,10-12, hampering both the understanding of circadian biology and the development of targeted therapeutics. Here we docked over 150 million virtual molecules against an MT1 crystal structure, prioritizing structural fit and chemical novelty. Thirty-eight high-ranking molecules were synthesized and tested, revealing ligands in the 470 pM to 6 μM range. Structure-based optimization led to two selective MT1 inverse agonists, topologically unrelated to previously explored chemotypes, that were tested in mouse models of circadian behavior. Unexpectedly, the MT1-selective inverse agonists advanced the phase of the mouse circadian clock by 1.3-1.5 hrs when given at subjective dusk, an agonist-like effect eliminated in MT1- but not in MT2-knockout mice. This study illustrates opportunities for modulating melatonin receptor biology via MT1-selective ligands, and for the discovery of new, in vivo-active chemotypes from structure-based screens of diverse, ultra-large libraries.

PMID:
32040955
DOI:
10.1038/s41586-020-2027-0

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