基于网络药理学及分子对接技术探讨五苓散治疗慢性心力衰竭的作用机制

Mechanism of Wuling Powder in the Treatment of Chronic Heart Failure Based on Network Pharmacology and Molecular Docking Technology

目的应用网络药理学及分子对接技术探讨五苓散治疗慢性心力衰竭(CHF)的作用机制。方法在中药系统药理学技术平台(TCMSP)检索五苓散主要成分及对应靶点;检索GeneCards、TTD、DrugBank、DisGeNET数据库,筛选CHF相关靶点;取疾病与药物交集靶点,构建韦恩图;应用Cytoscape 3.8.0软件建立五苓散药物-活性成分-靶点网络及药物成分-交集靶点网络,获得关键化合物;应用STRING平台构建交集靶点蛋白-蛋白相互作用(PPI)的网络图,分析网络图得到关键靶点;应用Metascape数据库对交集基因进行基因本体(GO)及京都基因与基因组百科全书(KEGG)通路富集分析。比较关键靶点及KEGG通路富集基因,选取主要靶点蛋白及关键化合物,应用CB-Dock平台进行分子对接验证。结果通过口服生物利用度(OB)及生物活性分子类药性(DL)筛选得到五苓散共有46个活性成分,共涉及63个作用靶点,与CHF重合的靶点有36个,得到谷甾醇、3β-乙酰氧基-白术酮、二氢槲皮素等10个关键化合物,NOS3、CASP3、PTGS2等10个关键靶点。GO分析得到与循环系统、细胞膜成分及蛋白质相关的注释条目。KEGG通路富集通路主要包括AGE-RAGE信号通路、细胞凋亡、白细胞介素-17(IL-17)信号通路、肿瘤坏死因子(TNF)信号通路等。分子对接结果显示,五苓散关键化合物与新型利尿剂托伐普坦,与治疗靶点均具有良好结合活性。结论五苓散包括多个活性成分,作用于多个靶点,通过抑制细胞凋亡、氧化应激、心肌重构、炎症通路等多种机制作用于CHF,体现了中药治疗疾病多成分、多靶点、多途径的特点。

Objective To explore the mechanism of Wuling Powder in the treatment of chronic heart failure(CHF)based on network pharmacology and molecular docking technology.Methods Main components and corresponding targets of Wuling Powder were searched on Traditional Chinese Medicines Systems Pharmacology Platform(TCMSP)website.The CHF-related targets were screened by GeneCards,TTD,DrugBank,and DisGeNET database.The intersection targets of disease and drugs were taken to construct the Venn figure.Cytoscape 3.8.0 software was used to establish the drug-active component-target network and the component-intersection target network of Wuling Powder to obtain the key compounds.The protein-protein interaction(PPI)network of intersection target was constructed by STRING platform,and the key targets were obtained by analyzing the network.Gene ontology(GO)and Kyoto encyclopedia of genes and genomes(KEGG)pathway enrichment analysis were performed for intersecting genes by Metascape database.The main target proteins and key compounds were selected by comparing the key targets and KEGG pathway enrichment genes.The CB-Dock platform was used for molecular docking verification.Results Forty-six active ingredients of Wuling Powder were obtained,involving 63 targets,among which there were 36 targets related with CHF.Ten key compounds were obtained,including beta-sitosterol,3β-acetoxyatractylone,taxifolin,etc.,and 10 key targets were obtained,including NOS3,CASP3,PTGS2,etc.GO analysis yielded annotation entries related to circulatory system,cell membrane components and proteins.KEGG pathways were enriched in advanced glycation end products-receptor for advanced glycation end products(AGE-RAGE)signaling pathway,apoptosis,interleukin-17 signaling pathway,tumor necrosis factor(TNF)signal pathway and so on.Molecular docking results showed that the key compounds of Wuling Powder possessed binding activity to the therapeutic target.Conclusion Wuling Powder contains multiple active components,and acts on multiple targets.It acts on CHF through inhibiting apoptosis,oxidative stress,myocardial remodeling,inflammatory pathways,and other mechanisms,reflecting the multi-component,multi-target,and multi-pathway characteristics of traditional Chinese medicine,providing reference for further exploration of Wuling Powder compound and related drugs in the treatment of CHF.