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Tytuł pozycji:

Virtual discovery of melatonin receptor ligands to modulate circadian rhythms.

Tytuł:
Virtual discovery of melatonin receptor ligands to modulate circadian rhythms.
Autorzy:
Stein RM; Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA.
Kang HJ; Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
McCorvy JD; Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA.
Glatfelter GC; Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo (SUNY), The State University of New York, Buffalo, NY, USA.; Designer Drug Research Unit, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD, USA.
Jones AJ; Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo (SUNY), The State University of New York, Buffalo, NY, USA.
Che T; Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Slocum S; Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Huang XP; Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Savych O; Enamine Ltd, Kiev, Ukraine.
Moroz YS; National Taras Shevchenko University of Kyiv, Kiev, Ukraine.; Chemspace, Monmouth Junction, NJ, USA.
Stauch B; Bridge Institute, USC Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, CA, USA.; Department of Chemistry, University of Southern California, Los Angeles, CA, USA.
Johansson LC; Bridge Institute, USC Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, CA, USA.; Department of Chemistry, University of Southern California, Los Angeles, CA, USA.
Cherezov V; Bridge Institute, USC Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, CA, USA.; Department of Chemistry, University of Southern California, Los Angeles, CA, USA.
Kenakin T; Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Irwin JJ; Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA.
Shoichet BK; Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA. .
Roth BL; Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. bryan_.
Dubocovich ML; Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo (SUNY), The State University of New York, Buffalo, NY, USA. .
Źródło:
Nature [Nature] 2020 Mar; Vol. 579 (7800), pp. 609-614. Date of Electronic Publication: 2020 Feb 10.
Typ publikacji:
Journal Article
Język:
English
Imprint Name(s):
Publication: Basingstoke : Nature Publishing Group
Original Publication: London, Macmillan Journals ltd.
MeSH Terms:
Ligands*
Circadian Rhythm/*physiology
Receptors, Melatonin/*agonists
Receptors, Melatonin/*metabolism
Animals ; Circadian Rhythm/drug effects ; Darkness ; Drug Evaluation, Preclinical ; Drug Inverse Agonism ; Female ; Humans ; Light ; Male ; Mice ; Mice, Knockout ; Molecular Docking Simulation ; Receptor, Melatonin, MT1/agonists ; Receptor, Melatonin, MT1/deficiency ; Receptor, Melatonin, MT1/genetics ; Receptor, Melatonin, MT1/metabolism ; Receptor, Melatonin, MT2/agonists ; Receptor, Melatonin, MT2/deficiency ; Receptor, Melatonin, MT2/genetics ; Receptor, Melatonin, MT2/metabolism ; Receptors, Melatonin/deficiency ; Receptors, Melatonin/genetics ; Small Molecule Libraries/pharmacology ; Substrate Specificity/genetics
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Grant Information:
R21 ES023684 United States ES NIEHS NIH HHS; R01 GM071896 United States GM NIGMS NIH HHS; UL1 TR001412 United States TR NCATS NIH HHS; R35 GM127086 United States GM NIGMS NIH HHS; R01 GM133836 United States GM NIGMS NIH HHS; R35 GM122481 United States GM NIGMS NIH HHS; U24 DK116195 United States DK NIDDK NIH HHS; R37 DA045657 United States DA NIDA NIH HHS; KL2 TR001413 United States TR NCATS NIH HHS
Substance Nomenclature:
0 (Ligands)
0 (Receptor, Melatonin, MT1)
0 (Receptor, Melatonin, MT2)
0 (Receptors, Melatonin)
0 (Small Molecule Libraries)
Entry Date(s):
Date Created: 20200211 Date Completed: 20200601 Latest Revision: 20211222
Update Code:
20240105
PubMed Central ID:
PMC7134359
DOI:
10.1038/s41586-020-2027-0
PMID:
32040955
Czasopismo naukowe
The neuromodulator melatonin synchronizes circadian rhythms and related physiological functions through the actions of two G-protein-coupled receptors: MT 1 and MT 2 . Circadian release of melatonin at night from the pineal gland activates melatonin receptors in the suprachiasmatic nucleus of the hypothalamus, synchronizing the physiology and behaviour of animals to the light-dark cycle 1-4 . The two receptors are established drug targets for aligning circadian phase to this cycle in disorders of sleep 5,6 and depression 1-4,7-9 . Despite their importance, few in vivo active MT 1 -selective ligands have been reported 2,8,10-12 , hampering both the understanding of circadian biology and the development of targeted therapeutics. Here we docked more than 150 million virtual molecules to an MT 1 crystal structure, prioritizing structural fit and chemical novelty. Of these compounds, 38 high-ranking molecules were synthesized and tested, revealing ligands with potencies ranging from 470 picomolar to 6 micromolar. Structure-based optimization led to two selective MT 1 inverse agonists-which were topologically unrelated to previously explored chemotypes-that acted as inverse agonists in a mouse model of circadian re-entrainment. Notably, we found that these MT 1 -selective inverse agonists advanced the phase of the mouse circadian clock by 1.3-1.5 h when given at subjective dusk, an agonist-like effect that was eliminated in MT 1 - but not in MT 2 -knockout mice. This study illustrates the opportunities for modulating melatonin receptor biology through MT 1 -selective ligands and for the discovery of previously undescribed, in vivo active chemotypes from structure-based screens of diverse, ultralarge libraries.
Comment in: Trends Pharmacol Sci. 2020 Jun;41(6):382-384. (PMID: 32340753)

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