Structure-based discovery of potent and selective melatonin receptor agonists
Category
Published on
Type
journal-article
Author
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
Citation
Patel, N. et al., 2020. Structure-based discovery of potent and selective melatonin receptor agonists. eLife, 9. Available at: http://dx.doi.org/10.7554/elife.53779.
Abstract
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.
DOI
Funding
NSF-STC Biology with X-ray Lasers (NSF-1231306)
