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Structure-based discovery of potent and selective melatonin receptor agonists. 2020

Nilkanth Patel, and Xi Ping Huang, and Jessica M Grandner, and Linda C Johansson, and Benjamin Stauch, and John D McCorvy, and Yongfeng Liu, and Bryan Roth, and Vsevolod Katritch
Department of Biological Sciences and Department of Chemistry, Bridge Institute, USC Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, United States.

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.

UI MeSH Term Description Entries
D004353 Drug Evaluation, Preclinical Preclinical testing of drugs in experimental animals or in vitro for their biological and toxic effects and potential clinical applications. Drug Screening,Evaluation Studies, Drug, Pre-Clinical,Drug Evaluation Studies, Preclinical,Drug Evaluations, Preclinical,Evaluation Studies, Drug, Preclinical,Evaluation, Preclinical Drug,Evaluations, Preclinical Drug,Medicinal Plants Testing, Preclinical,Preclinical Drug Evaluation,Preclinical Drug Evaluations,Drug Screenings,Screening, Drug,Screenings, Drug
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D001665 Binding Sites The parts of a macromolecule that directly participate in its specific combination with another molecule. Combining Site,Binding Site,Combining Sites,Site, Binding,Site, Combining,Sites, Binding,Sites, Combining
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D044094 Receptors, Melatonin A family of G-protein-coupled receptors that are specific for and mediate the effects of MELATONIN. Activation of melatonin receptors has been associated with decreased intracellular CYCLIC AMP and increased hydrolysis of PHOSPHOINOSITIDES. Melatonin Receptors,MT3 Receptor,Mel(1c) Receptor,Melatonin MT3 Receptor,Receptor, Mel1c,Receptor, Melatonin,Receptor, Melatonin, 1C,Receptor, Melatonin, MT3,MT3 Receptor, Melatonin,Mel1c Receptor,Melatonin Receptor,Receptor, MT3,Receptor, Melatonin MT3
D044122 Receptor, Melatonin, MT1 A melatonin receptor subtype that is primarily found in the HYPOTHALAMUS and in the KIDNEY. Melatonin MT1 Receptor,MT1 Receptor,Mel(1a)-Melatonin Receptor,MT1 Receptor, Melatonin,Receptor, MT1,Receptor, Melatonin MT1
D044123 Receptor, Melatonin, MT2 A melatonin receptor subtype primarily found expressed in the BRAIN and RETINA. Melatonin MT2 Receptor,MT2 Receptor,Mel 1b Receptor,Melatonin 1b Receptor,MT2 Receptor, Melatonin,Receptor, MT2,Receptor, Melatonin 1b,Receptor, Melatonin MT2
D055808 Drug Discovery The process of finding chemicals for potential therapeutic use. Drug Prospecting,Discovery, Drug,Prospecting, Drug

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