Virtual discovery of melatonin receptor ligands to modulate circadian rhythms

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 hy...

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Veröffentlicht in:	Nature (London) Jg. 579; H. 7800; S. 609 - 614
Hauptverfasser:	Stein, Reed M., Kang, Hye Jin, McCorvy, John D., Glatfelter, Grant C., Jones, Anthony J., Che, Tao, Slocum, Samuel, Huang, Xi-Ping, Savych, Olena, Moroz, Yurii S., Stauch, Benjamin, Johansson, Linda C., Cherezov, Vadim, Kenakin, Terry, Irwin, John J., Shoichet, Brian K., Roth, Bryan L., Dubocovich, Margarita L.
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	London Nature Publishing Group UK 01.03.2020 Nature Publishing Group
Schlagworte:	631/154/436/2387 631/92/2132 631/92/606 64 64/60 Agonists Animals Biological clocks Biological control systems Biology Chemical compounds Chemical synthesis Circadian rhythm Circadian Rhythm - drug effects Circadian Rhythm - physiology Circadian rhythms Crystal structure Darkness Discovery and exploration Drug development Drug Evaluation, Preclinical Drug Inverse Agonism Female G protein-coupled receptors Hormone receptors Humanities and Social Sciences Humans Hydrogen bonds Hypothalamus Inverse agonists Libraries Ligands Ligands (Biochemistry) Light Male Melatonin Melatonin receptors Mice Mice, Knockout Molecular Docking Simulation Molecular structure multidisciplinary Neuromodulation Optimization Pharmacology, Experimental Physiological aspects Physiology Pineal gland 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 Receptors, Melatonin - agonists Receptors, Melatonin - deficiency Receptors, Melatonin - genetics Receptors, Melatonin - metabolism Reentrainment Science Science (multidisciplinary) Small Molecule Libraries - pharmacology Structure Substrate Specificity - genetics Suprachiasmatic nucleus Synchronism Therapeutic targets United States
ISSN:	0028-0836, 1476-4687, 1476-4687
Online-Zugang:	Volltext
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Zusammenfassung:	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. A computational screen of an ultra-large virtual library against the structure of the melatonin receptor found nanomolar ligands, and ultimately two selective MT 1 inverse agonists that induced phase advancement of the mouse circadian clock when given at subjective dusk.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Author Contributions. These authors contributed equally. BKS, BLR, and MLD conceived the study. RMS performed the docking and structure-based optimization. JDM & HJK performed the initial binding and functional assays and analysis, assisted by TC, while AJJ performed the 2-[I125]-iodomelatonin and GTP-perturbation assays. SS performed the profiling studies. GCG performed the in vivo mouse pharmacology experiments and all animal husbandry. YSM and OS directed the compound synthesis, purification and characterization. BS, LCJ, VC, BLR, XPH, JDM determined and validated the structures of the MT1 and MT2 receptor types, and made them available before publication. JJI created the ultra-large libraries. BLR supervised the pharmacology studies; BKS supervised the docking and compound optimization; MLD supervised the binding studies and the in vivo mouse circadian rhythms experiments. MLD & GCG designed all in vivo experiments. RMS, BKS, MLD, GCG, JDM, HJK, and BLR wrote the paper with contributions from other authors.
ISSN:	0028-0836 1476-4687 1476-4687
DOI:	10.1038/s41586-020-2027-0