Structure-based discovery of potent and selective melatonin receptor agonists. Elife 2020 Mar 02;9
Date
03/03/2020Pubmed ID
32118583Pubmed Central ID
PMC7080406DOI
10.7554/eLife.53779Scopus ID
2-s2.0-85082095283 (requires institutional sign-in at Scopus site) 36 CitationsAbstract
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.
Author List
Patel N, Huang XP, Grandner JM, Johansson LC, Stauch B, McCorvy JD, Liu Y, Roth B, Katritch VAuthor
John McCorvy PhD Associate Professor in the Cell Biology Neurobiology and Anatomy department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Binding SitesDrug Discovery
Drug Evaluation, Preclinical
Humans
Receptor, Melatonin, MT1
Receptor, Melatonin, MT2
Receptors, Melatonin
Structure-Activity Relationship
