目的 采用网络药理学方法及分子对接技术探讨柏子养心丸治疗失眠症的潜在分子机制。方法 通过TCMSP数据库收集柏子养心丸的主要化学成分,经ADME筛选活性化合物并获取其作用靶点;搜索GeneCards、OMIM、PharmGKB、TTD、DrugBank数据库归并失眠症相关疾病基因;使用R语言程序对药物与疾病靶点取交集并上传至STRING平台构建蛋白相互作用(PPI)网络,应用Cytoscape软件进一步判别其核心模块;基于R语言平台对交集靶点进行基因本体(GO)功能与京都基因与基因组百科全书(KEGG)通路富集分析;利用Cytoscape软件构筑"柏子养心丸活性成分-失眠症基因"网络,并使用CytoNCA工具分析其关键药效组分与核心靶点;运用AutoDock套件进行网络关键成分与靶点的分子对接验证,并追溯PPI核心模块与其关联成分实行潜在成分与靶标的二次挖掘。结果 共筛选出槲皮素、山柰酚、木犀草素、黄芩素、柚皮素、β-谷甾醇、豆甾醇、7-O-甲基异微凸剑叶莎醇、7-甲氧基-2-甲基异黄酮等柏子养心丸的有效成分,治疗失眠症的作用靶点为前列腺素内过氧化物合酶2(PTGS2)、雌激素受体1(ESR1)、过氧化物酶体增殖物激活受体(PPARG)、环加氧酶1(PTGS1)等,各靶点与对应成分的对接活性较强。生物学通路主要涉及神经活性配体-受体相互作用通路、神经退行性变-多种疾病通路、脂质和动脉粥样硬化通路等。结论 从多角度全方位阐明柏子养心丸以"多成分、多靶点、多途径"的模式干预失眠症的潜在机制,可为其质量标准完善和机制深入考察夯实基础。

Objective To explore the mechanism of Baizi Yangxin Pills in treatment of insomnia based on network pharmacology and molecular docking technology. Methods To collect the primary chemical components of the Baizi Yangxin Pills through the TCMSP database, and screen the target by ADME. GeneCards, OMIM, PharmGKB, TTD, and DrugBank databases were searched and utilized to collate insomnia-related disease genes. R language program was applied to take the intersection of drug and disease targets and then uploaded to STRING platform to construct PPI network, and Cytoscape software was adopted to further discriminate its core modules. GO function and KEGG pathway enrichment analysis of intersectional targets were performed based on the R language interface. Cytoscape system was implemented to build up the network of "active components of Baizi Yangxin Pills-insomnia genes", and CytoNCA tool was used to diagnose its key ingredients and core targets. AutoDock suites were adopted to carry out molecular docking validation of network critical components and targets, and the PPI core modules were traced back to their linked ingredients to conduct secondary mining of potential compositions and targets. Results The effective components of the Baizi Yangxin Pills, such as quercetin, kaempferol, luteolin, baicalin, naringenin, β-sitosterol, stigmasterol, 7-O-methylisomucronulatol, 7-methoxy-2-methyl isoflavone were selected. The therapeutic targets of insomnia are PTGS2, ESR1, PPARG, PTGS1, etc. Each target has strong docking activity with the corresponding components. Biological pathways mainly involve neuroactive ligand-receptor interaction pathways, neurodegeneration-multiple disease pathways, lipid and atherosclerotic pathways, etc. Conclusion This study elucidates the potential mechanism of Baizi Yangxin Pills intervention in insomnia with the mode of "multi-component, multi-target and multi-pathway" from multiple perspectives, which can lay a solid foundation for the improvement of its quality standards and in-depth investigation of its mechanism.

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国家科技重大专项(民口)课题(2018ZX09301-011-003)