基于网络药理学和分子对接技术探讨瓜蒌薤白半夏汤治疗冠心病的作用机制

The Mechanism of Gualou Xiebai Banxia Decoction in the Treatment of Coronary Heart Disease Based on Network Pharmacology and Molecular Docking

目的基于网络药理学探讨瓜蒌薤白半夏汤治疗冠心病的作用机制。方法检索中药系统药理学技术平台(TCMSP)数据库中各中药化合物,并将化合物的靶蛋白信息导入UniProt网站进行基因名转换。将整合的数据导入Cytoscape 3.5.1软件,构建“中药-化合物-靶点”可视化网络图。登录DisGeNET、GeneCards、DrugBank、OMIM、GAD、TTD数据库对冠心病基因靶点进行检索,并将疾病与药物的交集靶点录入STRING网站构建蛋白-蛋白互作(PPI)网络,对节点信息进行分析与计算后筛选得到核心靶点。将靶点基因导入Metascape网站进行基因本体(GO)功能富集分析和京都基因与基因组百科全书(KEGG)通路富集分析,同时对通路进行预测。运用AutoDock 4.2、PyMOL 2.3.2软件对核心靶点进行分子对接验证。结果共筛选出瓜蒌薤白半夏汤包含的32种化合物,度值较高的是β-谷甾醇、豆甾醇、柚皮素等。通过Cytoscape 3.5.1软件构建的PPI网络包含98个节点、1318条边,核心靶点为前列腺素内过氧化物合酶2(PTGS2)、磷脂酰肌醇3-激酶催化亚基a(PIK3CA)、基质金属蛋白酶2(MMP2)、血管内皮生长因子A(VEGFA)等。通过GO及KEGG富集筛选出与冠心病相关的磷脂酰肌醇3-激酶-蛋白激酶B(PI3K-Akt)等10条核心通路,并采用分子对接方法对结果进行了验证。结论柚皮素、β-谷甾醇、豆甾醇、松柏苷、槲皮素可能是瓜蒌薤白半夏汤治疗冠心病发挥关键作用的化合物,可能通过作用于PTGS2、PIK3CA、MMP2、VEGFA等靶点对肾素-血管紧张素系统(RAS)、RAS相关蛋白-A(Rap1)、血管内皮生长因子(VEGF)等通路进行调控,而PI3K-Akt可能是瓜蒌薤白半夏汤治疗冠心病的核心通路。

Objective To explore the mechanism of Gualou Xiebai Banxia Decoction in the treatment of coronary heart disease based on network pharmacology and molecular docking.Methods All traditional Chinese medicine compounds were searched based on the TCMSP database,and the target protein information of the compounds was imported into UniProt website for gene name conversion.The integrated data were imported into Cytoscape 3.5.1 software to construct the"herb-compound-target"genes visual network diagram.The gene targets of coronary heart disease were retrieved by logging into DisGeNET,GeneCards,DrugBank,OMIM,GAD,and TTD databases,and the intersection targets of diseases and drugs were recorded in STRING website to construct protein-protein interaction(PPI)network.The node information was analyzed and calculated,and the core targets were screened.Target genes were imported into Metascape website for Gene Ontology(GO)enrichment analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis to predict pathways.AutoDock 4.2 and PyMOL 2.3.2 were used for docking molecule and verifying the core targets.Results A total of 32 compounds includingβ-sitosterol,stigmasterol,and naringin were screened out from Gualou Xiebai Banxia Decoction.The PPI network constructed by Cytoscape 3.5.1 software contained 98 nodes and 1318 edges,and the core targets were prostaglandin endoperoxide synthase 2(PTGS2),phosphatidylinositol 3-kinase catalytic subunit a(PIK3CA),matrix metalloproteinase 2(MMP2),and vascular endothelial growth factor A(VEGFA).Ten core pathways such as phosphatidylinositol 3-kinase(PI3K)-protein kinase B(Akt)related to coronary heart disease were screened by GO and KEGG enrichment,and the results were verified by molecular docking technology.Conclusion Naringin,β-sitosterol,sitosterol,conitin,and quercetin might play a key role in the treatment of coronary heart disease by acting on PTGS2,PIK3CA,MMP2,and VEGFA to regulate renin angiotensin system(RAS),RAS-related protein-A(Rap1),vascular endothelial growth factor(VEGF),and other pathways.PI3K-Akt might be the core pathway of Gualou Xiebai Banxia Decoction in the treatment of coronary heart disease.