Virtual discovery of melatonin receptor ligands to modulate circadian rhythms
Virtual discovery of melatonin receptor ligands to modulate circadian rhythms
复制标题
DOI：
10.1038/s41586-020-2027-0
复制
发表时间：
2020-03-18
期刊：
影响因子：
64.8
通讯作者：
Dubocovich, Margarita L.
中科院分区：
文献类型：
--
作者：
Stein, Reed M.;Kang, Hye Jin;Dubocovich, Margarita L.
褪黑激素通过两种G蛋白偶联受体MT 1和MT 2的作用调节昼夜节律和相关的生理功能。松果体在夜间释放的褪黑激素的昼夜节律激活了下丘脑视交叉上核中的褪黑激素受体，使动物的生理和行为与明暗周期同步（1-4）。这两种受体是确定的药物靶标，用于将睡眠障碍（5，6）和抑郁症（1- 4，7 -9）的昼夜节律相位与该周期对齐。尽管它们很重要，但很少有体内活性MT 1选择性配体的报道（2，8，10 -12），这阻碍了对昼夜节律生物学的理解和靶向治疗的开发。在这里，我们将超过1.5亿个虚拟分子对接到MT 1晶体结构上，优先考虑结构匹配和化学新奇。在这些化合物中，合成并测试了38种高级分子，揭示了效力范围从470皮摩尔到6微摩尔的配体。基于结构的优化产生了两种选择性MT 1反向激动剂--它们与之前探索的化学型在拓扑上不相关--在昼夜节律再诱导的小鼠模型中充当反向激动剂。值得注意的是，我们发现这些MT 1选择性反向激动剂在主观黄昏时给予小鼠生物钟的相位提前1.3-1.5小时，在MT 1中消除的激动剂样作用，但在MT 2敲除小鼠中没有。这项研究说明了通过MT 1选择性配体调节褪黑激素受体生物学的机会，以及从基于结构的多样化超大库筛选中发现以前未描述的体内活性化学型的机会。针对褪黑激素受体结构的超大虚拟库的计算筛选发现了纳摩尔配体，并且最终发现了两种选择性MT 1反向激动剂，其在主观黄昏时给予时诱导小鼠昼夜节律钟的相位提前。
The neuromodulator melatonin synchronizes circadian rhythms and related physiological functions through the actions of two G-protein-coupled receptors: MT1 and MT2. Circadian release of melatonin at night from the pineal gland activates melatonin receptors in the suprachiasmatic nucleus of the hypothalamus, synchronizing the physiology and behaviour of animals to the light-dark cycle(1-4). The two receptors are established drug targets for aligning circadian phase to this cycle in disorders of sleep(5,6) and depression(1-4,7-9). Despite their importance, few in vivo active MT1-selective ligands have been reported(2,8,10-12), hampering both the understanding of circadian biology and the development of targeted therapeutics. Here we docked more than 150 million virtual molecules to an MT1 crystal structure, prioritizing structural fit and chemical novelty. Of these compounds, 38 high-ranking molecules were synthesized and tested, revealing ligands with potencies ranging from 470 picomolar to 6 micromolar. Structure-based optimization led to two selective MT1 inverse agonists-which were topologically unrelated to previously explored chemotypes-that acted as inverse agonists in a mouse model of circadian re-entrainment. Notably, we found that these MT1-selective inverse agonists advanced the phase of the mouse circadian clock by 1.3-1.5 h when given at subjective dusk, an agonist-like effect that was eliminated in MT1- but not in MT2-knockout mice. This study illustrates the opportunities for modulating melatonin receptor biology through MT1-selective ligands and for the discovery of previously undescribed, in vivo active chemotypes from structure-based screens of diverse, ultralarge libraries. A computational screen of an ultra-large virtual library against the structure of the melatonin receptor found nanomolar ligands, and ultimately two selective MT1 inverse agonists that induced phase advancement of the mouse circadian clock when given at subjective dusk.