Structure-based discovery of potent and selective melatonin receptor agonists

eLife

Jessica M Grandner¹  Bryan Roth¹  John D McCorvy²  Nilkanth Patel²  Linda C Johansson²  Benjamin Stauch²  Xi Ping Huang³  Vsevolod Katritch³  Yongfeng Liu³ 

[1] 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 Pharmacology, University of North Carolina Chapel Hill Medical School, Chapel Hill, United States;

关键词: GPCR;    virtual ligand screening;    melatonin;    biased signaling;   

DOI  :  10.7554/eLife.53779

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown