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Melatonin receptors MT 1  and MT 2  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 EC 50  of 0.36 nM. Six of these molecules displayed selectivity for MT 2  over MT 1 . Moreover, two most potent agonists, including  21  and a close derivative of melatonin,  28 , had dramatically reduced arrestin recruitment at MT 2 , while compound  37  was devoid of G i  signaling at MT 1 , 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.

Structure-based discovery of potent and selective melatonin receptor agonists