Department of Biological Sciences and Department of Chemistry, Bridge Institute, USC Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, United States.
Department of Pharmacology, University of North Carolina Chapel Hill Medical School, Chapel Hill, United States.
Elife. 2020 Mar 2;9:e53779. doi: 10.7554/eLife.53779.
Melatonin receptors MT and MT 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 reaching EC of 0.36 nM. Six of these molecules displayed selectivity for MT over MT. Moreover, two most potent agonists, including and a close derivative of melatonin, , had dramatically reduced arrestin recruitment at MT, while compound was devoid of G signaling at MT, 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.
褪黑素受体 MT 和 MT 参与同步生物钟节律，是治疗睡眠和情绪障碍、2 型糖尿病和癌症的重要靶点。在这里，我们使用最近解决的高分辨率 3D 晶体结构，对激动剂结合的 MT 受体进行了大规模基于结构的虚拟筛选，以寻找新的配体化学型。对 62 个筛选候选物进行的实验测试发现了 10 种新的激动剂化学型，它们对 MT 受体具有亚毫摩尔的效力，其中化合物达到 EC 的 0.36 nM。这 6 种分子对 MT 表现出选择性，而不是 MT。此外，两种最有效的激动剂，包括 和褪黑素的一个近衍生物 ，在 MT 上大大减少了 arrestin 的募集，而化合物在 MT 上没有 G 信号，暗示了偏向信号。这项研究验证了激动剂结合的 MT 受体结构中的正位口袋在基于结构的选择性激动剂发现中的适用性。
