应用计算机模拟研究牛膝在骨关节炎中的痿痹同治作用

Application of Computer Simulation in Exploring the Effects of Achyranthis Bidentatae Radix on Simultaneously Treating Wei Syndrome and Bi Syndrome of Osteoarthritis

目的:从分子水平探讨牛膝在骨关节炎中痿痹同治的药效物质基础、作用靶点及作用方式。方法:①从中国知网和PubMed等数据库中,检索73个牛膝的化学成分,构建牛膝的化学成分数据集;从DrugBank数据库中搜索与骨关节炎治疗相关的药物分子,其中,刺激关节软骨中蛋白多糖合成的药物分子3个,用于构建治痿的药物分子数据集,以及抗炎镇痛的药物分子28个,用于构建治痹的药物分子数据集;依托定量构效关系及主成分分析平台,分析牛膝化学成分数据集和药物分子数据集的化学空间。②以治痹直接相关的白介素-1β、白介素-6、肿瘤坏死因子-α,以及治痿直接相关的基质金属蛋白酶-1、基质金属蛋白酶-3、转化生长因子-β1为靶点,利用分子对接和生物网络等平台,研究其与牛膝中化学成分的相互作用,并构建牛膝治痿和治痹的化合物-靶点网络,分析牛膝治疗骨关节炎的药效物质基础、靶点和作用方式。结果:①相对于药物分子数据集,牛膝化学成分数据集在化学空间上具有更好的分散性,且在后方存在与治痿的药物分子数据集相似或相近的化学空间,在底部存在与治痹的药物分子数据集相似或相近的化学空间,揭示了牛膝具有治痿和治痹作用的可能性。②化合物-靶点网络显示了牛膝的药效物质基础主要为皂苷类、植物甾酮类、黄酮类和生物碱化合物,且治痹和治痿的化合物个数分别为37和26,同时具有治痹和治痿作用的化合物个数为20,能作用的靶点最大数目达到6。其中,牛膝治痹化合物-靶点网络的重要化合物节点为黄酮类物质葛根素、黄芩苷、槲皮素-3-O-芸香糖苷和山柰酚-3-O-葡萄糖苷,其重要靶点节点为白介素-1β和肿瘤坏死因子-α;牛膝治痿化合物-靶点网络的重要化合物节点为黄酮类物质黄芩苷,其重要靶点节点为基质金属蛋白酶-1。结论:计算机模拟直观地显示了牛膝治疗骨关节炎可能是通过类似混杂药物和组合药物的方式达到痿痹同治的多靶点作用,为其治疗骨关节炎的临床应用和新药开发提供依据。

Objective: To explore the pharmacodynamic material basis, action targets and modes of Achyranthis Bidentatae Radix(Niuxi in Chinese) on the simultaneous treatment of Wei syndrome and Bi syndrome in osteoarthritis(OA) from the molecular level.Methods: ① Seventy-three chemical components of Niuxi were retrieved from the databases of China National Knowledge Infrastructure(CNKI) and PubMed, and to built molecular dataset of Niuxi. Meanwhile, three drugs related to articular cartilage proteoglycan synthesis stimulation(the treatment for Wei syndrome) and twenty-eight drugs related to anti-inflammation analgesia(the treatment for Bi syndrome) on OA were searched from the DrugBank database, and their corresponding molecular datasets of treating Wei syndrome and Bi syndrome were also built. Based on the platforms of quantitative structure-activity relationship and principal component analysis, the distributions of the above datasets were analyzed in the chemical space. ② Matrix metalloproteinase-1(MMP-1), matrix metalloproteinase-3(MMP-3), and transforming growth factor beta-1(TGF-β1) were chosen as the targets of treating Wei Syndrome of OA,while interleukine-1 beta(IL-1β),interleukine-6(IL-6), tumor necrosis factor-alpha(TNF-α) were chosen as the targets of treating Bi syndrome of OA. The platforms of molecular docking and biological network were used to study the interactions between the Niuxi compounds and above targets, and Niuxi compound-target networks related to the treatment of Wei syndrome and Bi syndrome were constructed to analyze the pharmacodynamic material basis, action targets and modes of Niuxi in the therapy of OA. Results: ① Comparison of the chemical space distributions between molecular datasets of Niuxi and drugs indicated that the chemical space distributions of the former were more diverse than those of the latter, and the former were the same, or close to the latter with the treatment of Wei syndrome at the back of chemical space, while the former were the same, or close to the latter with the treatment of Bi syndrome at the bottom back corner of chemical space. These revealed the possible effects of Niuxi on Wei syndrome and Bi syndrome of OA.② The compound-target networks showed that the main pharmacodynamic material basis of Niuxi contained saponins, phytosterones,flavonoids and alkaloids. Meanwhile, the Niuxi compound numbers of treating Bi syndrome and Wei syndrome were thirty-seven and twenty-six, respectively. Among them, twenty compounds could simultaneously treating Bi syndrome and Wei syndrome of OA. The maximum number of targets interacting with them was six. Furthermore, in the compound-target network of Niuxi in treating Bi syndrome of OA, the key compound nodes of Niuxi were puerarin, baicalin, quercetin-3-O-rutinose and kaempferol-3-O-glucoside,which belonged to flavonoids, and the key target nodes were IL-1β and TNF-α. In the compound-target network of Niuxi in treating Wei syndrome of OA, the key compound node of Niuxi was baicalin, which belonged to flavonoids, and the key target node was MMP-1.Conclusion: Computer simulation intuitively showed the multi-target effects of Niuxi in simultaneously treating Wei syndrome and Bi syndrome of OA through the modes like promiscuous drug and combination drug. This could provide a basis for Niuxi therapeutic for OA and new drug development from Niuxi.