美国布法罗大学（SUNY）Margarita L. Dubocovich、北卡罗来纳大学教堂山医学院Bryan L. Roth和美国加州大学旧金山分校Brian K. Shoichet课题组合作揭示褪黑素受体配体调节昼夜节律的虚拟发现。2020年2月10日，《自然》在线发表了这一成果。

他们将超过1.5亿个虚拟分子与MT1晶体结构对接，从而优先考虑结构配合和化学新颖性。合成并测试了38个高级分子，揭示了470 pM至6μM范围内的配体。基于结构的优化产生了两个选择性的MT1反向激动剂，它们在拓扑结构上与以前探索的化学型无关，已在昼夜节律行为的小鼠模型中进行了测试。出乎意料的是，在主观黄昏时给药，MT1选择性反向激动剂使小鼠生物钟提前了1.3-1.5小时，在MT1中类似激动剂的作用消除，但在MT2敲除小鼠中却没有。这项研究说明了通过MT1选择性配体调节褪黑激素受体生物学的机会，以及从各种超大型文库的基于结构的筛选中发现新的体内活性化学型的机会。

据了解，神经调节褪黑素通过对两个G蛋白偶联受体MT1和MT2的作用来同步昼夜节律和相关的生理功能。夜间从松果体中有节律的释放高水平的褪黑激素会激活下丘脑上眼睑上核中的褪黑激素受体，使生理和行为与明暗循环同步。这两种受体是使睡眠障碍和抑郁症中的昼夜节律相一致的既定药物靶标。尽管它们具有重要意义，但几乎没有体内活性MT1选择性配体被报道，这阻碍了对昼夜节律生物学的理解和靶向疗法的发展。

附：英文原文

Title: Virtual discovery of melatonin receptor ligands to modulate circadian rhythms

Author: Reed M. Stein, Hye Jin Kang, John D. McCorvy, Grant C. Glatfelter, Anthony J. Jones, Tao Che, Samuel Slocum, Xi-Ping Huang, Olena Savych, Yurii S. Moroz, Benjamin Stauch, Linda C. Johansson, Vadim Cherezov, Terry Kenakin, John J. Irwin, Brian K. Shoichet, Bryan L. Roth, Margarita L. Dubocovich

Issue&Volume: 2020-02-10

Abstract: The neuromodulator melatonin synchronizes circadian rhythms and related physiological functions via actions at two G protein-coupled receptors: MT1 and MT2. Circadian release of high nighttime levels of melatonin from the pineal gland activates melatonin receptors in the suprachiasmatic nucleus of the hypothalamus, synchronizing physiology and behavior to the light-dark cycle1–4. The two receptors are established drug targets for aligning circadian phase in disorders of sleep5,6 and depression7,1–4,8,9. Despite their importance, few if any in vivo active MT1 selective ligands have been reported2,8,10–12, hampering both the understanding of circadian biology and the development of targeted therapeutics. Here we docked over 150 million virtual molecules against an MT1 crystal structure, prioritizing structural fit and chemical novelty. Thirty-eight high-ranking molecules were synthesized and tested, revealing ligands in the 470 pM to 6 μM range. Structure-based optimization led to two selective MT1 inverse agonists, topologically unrelated to previously explored chemotypes, that were tested in mouse models of circadian behavior. Unexpectedly, the MT1-selective inverse agonists advanced the phase of the mouse circadian clock by 1.3-1.5 hrs when given at subjective dusk, an agonist-like effect eliminated in MT1- but not in MT2-knockout mice. This study illustrates opportunities for modulating melatonin receptor biology via MT1-selective ligands, and for the discovery of new, in vivo-active chemotypes from structure-based screens of diverse, ultra-large libraries.

DOI: 10.1038/s41586-020-2027-0

Source: https://www.nature.com/articles/s41586-020-2027-0