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.
All chemical structures of candidate hits and chemical quality control information is deposited as Supplementary InformationAll data generated and analysed during this study is included in the main manuscript or supplementary files.
- Bryan Roth
- Bryan Roth
- Benjamin Stauch
- Linda C Johansson
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Nir Ben-Tal, Tel Aviv University, Israel
© 2020, Patel et al.
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