基于网络药理学和分子对接探讨六味地黄丸治疗糖尿病肾病的作用机制研究

Study on Mechanism of the Effect of Liuwei Dihuang Pill on Diabetic Nephropathy Based on Network Pharmacology and Molecular Docking

关键词:  网络药理学  分子对接  六味地黄丸  糖尿病肾病

Key words:  network pharmacology  molecular docking  Liuwei Dihuang pill  diabetic nephropathy

摘要:

目的 运用网络药理学和分子对接方法探讨六味地黄丸治疗糖尿病肾病（diabetic nephropathy，DN））的作用机制。方法 通过检索多个数据库及查阅文献筛选出六味地黄丸活性成分和对应靶点，借助Genecard、OMIM和Drugbank数据库收集DN作用靶点并通过Venny 2.1软件筛选出药物-疾病共同作用靶点。随后，利用STRING和Cytoscape软件分析和构建蛋白质-蛋白质相互作用网络并使用CytoNCA插件进行拓扑分析刷选出核心靶点。然后，利用ClueGO插件进行GO （GO Ontology）功能富集分析和KEGG-（Kyoto Encyclopedia of Genes and Genomes）通路分析。最后，使用AutoDock软件通过分子对接验证活性化合物与核心靶点的结合能力。结果 六味地黄丸40个活性成分通过调控128个DN相关靶点，尤其是通过调控28个核心靶点，参与调控体内基因转录、细胞凋亡和增殖、信号转导、炎症反应及蛋白质磷酸化等生物学过程，干预肿瘤、AGE-RAGE、IL-17、MAPK、HIF-1、Toll样受体等信号通路发挥治疗DN的作用。分子对接验证了5种活性化合物与其作用的关键靶点具有可靠的亲和力。结论 推测六味地黄丸治疗DN具有多成分-多靶点-多途径的特点，为进一步研究六味地黄丸治疗DN的分子机制提供了新思路和新方向。

Abstract:

OBJECTIVE To explore the synergistic mechanism of Liuwei Dihuang pill in the treatment of diabetic nephropathy(DN) by using network pharmacology and molecular docking method. METHODS The active ingredients and corresponding targets of Liuwei Dihuang pills were screened out by searching multiple databases and literature. With the help of Genecard, OMIM and Drugbank databases, the targets of diabetic nephropathy were collected and the drug-disease joint targets were screened through Venny 2.1 software. Subsequently, STRING and Cytoscape software was used to analyze and construct protein-protein interaction network, and use CytoNCA plug-in for topology analysis to select core targets. Then, the GO Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analysis were performed by using ClueGO tool. Finally, the binding capacity between active components and key targets was validated by molecular docking using AutoDock. RESULTS Forty active components involved in 128 targets related to DN were identified in Liuwei Dihuang pill. Especially by regulating 28 core targets, participating in the regulation of biological processes such as gene transcription, apoptosis and proliferation, signal transduction, inflammation, and protein phosphorylation in the body, intervening in tumors, AGE-RAGE, IL-17, MAPK, signal pathways such as HIF-1 and Toll-like receptors to play a role in the treatment of DN. The molecular docking verified that the 5 active compounds had reliable affinity with corresponding targets. CONCLUSION The treatment of DN with Liuwei Dihuang pill has the characteristics of multi component-multi target-multi pathway, which provides new ideas and new directions for further research on the molecular mechanism of Liuwei Dihuang pill in the treatment of DN.