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.
Highlights
The type 1A and 1B melatonin receptors (MT1 and MT2) are G protein-coupled receptors (GPCRs) that respond to the neurohormone melatonin (N-acetyl-5-methoxytryptamine) (Pevet, 2016; Reppert et al, 1994)
Our results demonstrate that structure-based virtual ligand screen (VLS) approach can yield novel, highly potent and selective ligand chemotypes with potential utility as chemical probes with distinct properties and candidate leads for the treatment of circadian rhythm related sleep and mood disorders
To evaluate the ability of the structure-based receptor models to recognize high-affinity melatonin receptor ligands, we performed extensive docking of a subset of known ligands of MT1 and MT2 receptors (Figure 1—figure supplement 1) into (i) the unmodified 3D structures obtained from X-ray crystallography (MT1_Xtal, MT2_Xtal), as well as (ii) into the receptor models where the ligandbinding pocket was optimized by conformational modeling (MT1_Opt, MT2_Opt)
Summary
The type 1A and 1B melatonin receptors (MT1 and MT2) are G protein-coupled receptors (GPCRs) that respond to the neurohormone melatonin (N-acetyl-5-methoxytryptamine) (Pevet, 2016; Reppert et al, 1994). The three-dimensional structures of MT1 and MT2 were determined using an X-ray freeelectron laser (XFEL), providing atomic-level details of receptor-ligand interactions (Johansson et al, 2019; Stauch et al, 2019) Both receptors were resolved in complexes with agonists – agomelatine, 2-phenylmelatonin, 2-iodomelatonin and ramelteon, thermostabilizing mutations that were necessary for crystallization rendered these receptors functionally inactive. Our results demonstrate that structure-based VLS approach can yield novel, highly potent and selective ligand chemotypes with potential utility as chemical probes with distinct properties and candidate leads for the treatment of circadian rhythm related sleep and mood disorders
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