基于网络药理学及分子对接探讨瓜蒌-薤白治疗冠心病的作用机制

Mechanism of Gualou-Xiebai in Treatment of Coronary Heart Disease Based on Network Pharmacology and Molecular Docking

目的:运用网络药理学及分子对接探索瓜蒌-薤白治疗冠心病的作用机制。方法:应用中药系统药理学数据库与分析平台(TCMSP)和BATMAN-TCM筛选符合口服生物利用度(OB)≥30%、类药性(DL)≥0.18的瓜蒌-薤白活性成分及作用靶点;使用GeneCards数据库在线获取冠心病相关靶点;将瓜蒌-薤白与冠心病的交集靶点导入STRING数据库构建蛋白质-蛋白质相互作用(PPI)网络,使用Cytoscape分析网络的核心靶点,运用ClueGO及DAVID在线数据库对交集靶点进行基因本体(GO)富集分析和京都基因和基因组百科全书(KEGG)通路富集分析,最后使用Autodock软件对核心活性成分及作用靶点进行分子对接验证。结果:瓜蒌-薤白中共得到22种活性成分,201个靶点,与冠心病相关靶点116个,在构建核心靶点PPI网络后得到包括肿瘤坏死因子(TNF)、苏氨酸蛋白激酶1(AKT1)、丝裂原活化蛋白激酶3(MAPK3)、白细胞介素-6(IL-6)、肿瘤蛋白P53(TP53)、血管内皮生长因子A(VEGFA)、上皮生长因子A(EGFA)等核心靶点,涉及生物学过程对缺氧的反应、对药物的反应、聚合酶Ⅱ启动子转录的正调控和衰老等,KEGG通路包括HIF-1信号通路、TNF信号通路和cancer信号通路等,分子对接表明活性成分中槲皮素、β-谷甾醇、香叶木素、柚皮素、羟基芜花素活性成分可作用于磷酸肌醇3激酶(PIK3CG)、丝裂原活化蛋白激酶1(MAPK1)、环加氧酶2(PTGS2)、MAPK3、TNF和AKT1等核心靶点。结论:瓜蒌-薤白中槲皮素、β-谷甾醇、香叶木素、柚皮素、羟基芜花素可能作用于PIK3CG、MAPK1、PTGS2、MAPK3、TNF和AKT1而影响TNF、HIF-1和晚期糖基化终产物及受体(AGE/RAGE)等通路发挥治疗冠心病的作用。

Objective:To explore the mechanism of Gualou-Xiebai in the treatment of coronary heart disease(CHD)by network pharmacology and molecular docking.Methods:Traditional Chinese Medicines Systems Pharmacology(TCMSP)and BATMAN-TCM were used to screen out the active components and targets of Gualou-Xiebai in accordance with oral bioavailability(OB)value≥30% and drug-likeness(DL)value≥0.18.The CHD-related targets were obtained online by GeneCards database,and the intersection targets of Gualou-Xiebai and CHD were imported into the STRING database to construct a protein-protein interaction(PPI)network.The core targets of the network were analyzed by Cytoscape.The Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analyses of the intersection targets were carried out by using the online databases of ClueGO and DAVID.Finally,the molecular docking verification of the core active components and action targets was carried out by Autodock.Results:In Guualou-Xiebai,22 active components,201 targets,and 116 CHD-related targets were obtained.After the construction of the PPI network,the core targets including tumor necrosis factor(TNF),protein kinase B1(AKT1),mitogen-activated protein kinase(MAPK)3,interleukin-6(IL-6),tumor protein 53(TP53),vascular endothelial growth factor-A(VEGF-A),and epidermal growth factor-A(EGF-A)were obtained,which were involved in the response of biological processes to response to hypoxia,response to drugs,positive regulation of transcription from polymerase Ⅱ promoter,and aging of polymerase Ⅱ promoter.KEGG pathways involved hypoxia inducible factor-1(HIF-1)signaling pathway,TNF signaling pathway,and pathways in cancer.Molecular docking showed that the active components including quercetin,β-sitosterol,diosmetin,naringenin,and hydroxygenkwanin could act on the core targets including PIK3 CG,MAPK1,prostaglandin-endoperoxide synthase 2(PTGS2),MAPK3,TNF,and AKT1.Conclusion:The quercetin,β-sitosterol,diosmetin,naringenin,and hydroxygenkwanin in Gualou-Xiebai may act on PIK3 C,MAPK1,PTGS2,MAPK3,TNF,and AKT1 to affect TNF,HIF-1,and AGE/RAGE pathways in the treatment of CHD.