Chen Yahong, Wang Xiaohong, Zhai Haifeng, Zhang Yanling, Huang Jianmei
School of Chinese Materia Medica, Beijing University of Chinese Medicine, Yangguang South Road, Fangshan District, Beijing 102488, China.
National Institute on Drug Dependence, Peking University, 38#, Xueyuan Road, Haidian District, Beijing 100191, China.
ACS Omega. 2021 Oct 29;6(44):29940-29954. doi: 10.1021/acsomega.1c04468. eCollection 2021 Nov 9.
Natural small-molecule phenols (NSMPs) possess certain ubiquitous bioactivities including the anxiolytic effect. Ryanodine receptor 1 (RyR1) may be one of the potentially critical pharmacological targets for studying the anxiolytic activity of NSMPs. However, detailed molecular mechanisms of NSMPs have not been fully clarified. This research was intended to identify potent hRyR1 agonists from NSMPs and investigate whether RyR1 plays a role in their anxiolytic effect. Homology modeling and molecular docking analysis were performed using Accelrys Discovery Studio 2.5. The most appropriate concentrations of NSMPs to activate RyR1 were measured using the MTT assay. Fluorescence analyses of the intracellular calcium levels and western blotting analysis were carried out to validate whether NSMPs could regulate the calcium flux to some extent by activating RyR1. The results demonstrated that xanthotoxol and 5-hydroxy-1,4-naphthalenedione can be screened as hit compounds for potential agonists of hRyR1 to exert the anxiolytic effect. In conclusion, NSMPs might be a kind of pharmacological signal carrier, acting on RyR1 as an agonist and resulting in calcium ion mobilization from intracellular calcium ion store.
天然小分子酚类化合物（NSMPs）具有某些普遍存在的生物活性，包括抗焦虑作用。兰尼碱受体1（RyR1）可能是研究NSMPs抗焦虑活性的潜在关键药理学靶点之一。然而，NSMPs的详细分子机制尚未完全阐明。本研究旨在从NSMPs中鉴定出有效的人RyR1激动剂，并研究RyR1是否在其抗焦虑作用中发挥作用。使用Accelrys Discovery Studio 2.5进行同源建模和分子对接分析。使用MTT法测定激活RyR1的NSMPs的最合适浓度。进行细胞内钙水平的荧光分析和蛋白质印迹分析，以验证NSMPs是否可通过激活RyR1在一定程度上调节钙通量。结果表明，花椒毒素和5-羟基-1,4-萘二酮可被筛选为hRyR1潜在激动剂的命中化合物，以发挥抗焦虑作用。总之，NSMPs可能是一种药理学信号载体，作为激动剂作用于RyR1，导致钙离子从细胞内钙离子储存库中动员出来。
