Department of Biological Sciences and Department of Chemistry, Bridge Institute, USC Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, United States
Department of Pharmacology, University of North Carolina Chapel Hill Medical School, Chapel Hill, United States; National Institute of Mental Health Psychoactive Drug Screening Program, Department of Pharmacology, University of North Carolina Chapel Hill Medical School, Chapel Hill, United States
Department of Biological Sciences and Department of Chemistry, Bridge Institute, USC Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, United States
Department of Biological Sciences and Department of Chemistry, Bridge Institute, USC Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, United States
Department of Biological Sciences and Department of Chemistry, Bridge Institute, USC Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, United States
Department of Pharmacology, University of North Carolina Chapel Hill Medical School, Chapel Hill, United States; National Institute of Mental Health Psychoactive Drug Screening Program, Department of Pharmacology, University of North Carolina Chapel Hill Medical School, Chapel Hill, United States
Yongfeng Liu
Department of Pharmacology, University of North Carolina Chapel Hill Medical School, Chapel Hill, United States; National Institute of Mental Health Psychoactive Drug Screening Program, Department of Pharmacology, University of North Carolina Chapel Hill Medical School, Chapel Hill, United States
Bryan Roth
Department of Pharmacology, University of North Carolina Chapel Hill Medical School, Chapel Hill, United States; National Institute of Mental Health Psychoactive Drug Screening Program, Department of Pharmacology, University of North Carolina Chapel Hill Medical School, Chapel Hill, United States; Division of Chemical Biology and Medicinal Chemistry, University of North Carolina Chapel Hill Medical School, Chapel Hill, United States
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.
