基于网络药理学和分子对接研究金丹健肝胶囊治疗肝纤维化的作用机制

Mechanism of Jindanjiangan Capsule in the treatment of hepatic fibrosis based on network pharmacology and molecular docking

目的利用网络药理学和分子对接技术阐明金丹健肝胶囊治疗肝纤维化可能的作用机制。方法通过中药系统药理学数据库分析平台(http://tcmspw.com/tcmsp.php)和HERB数据库(http://herb.ac.cn)检索金丹健肝胶囊活性成分和靶点,通过DisGeNET、药物靶点数据库(Therapeutic Target Database,TTD)筛选肝纤维化疾病靶点;将金丹健肝胶囊活性成分的药物靶点与疾病靶点匹配,所得共同靶点导入STRING数据库平台构建蛋白质相互作用(protein pro⁃tein interaction,PPI)网络;利用Cytoscape3.9.1软件CytoNCA工具进行拓扑分析,筛选关键靶点;应用Cytoscape3.9.1软件构建“中药-关键活性成分-关键靶点”网络图;通过DAVID平台(https://david.ncifcrf.gov)对关键靶点进行KEGG(Kyoto encyclopedia of genes and genomes)富集分析;采用LeDock软件对活性成分与靶点进行分子对接验证。结果筛选获得金丹健肝胶囊180个潜在活性成分,1340个靶点,肝纤维化疾病1060个靶点,两者共同靶点273个。PPI网络互作筛选出与肝纤维化相关的关键靶点29个,并通过KEGG分析及分子对接验证。金丹健肝胶囊通过异牡荆素、槲皮素7-O-β-D-葡萄糖苷、(3S,6S)-3-(苄基)-6-(4-羟基苄基)哌嗪-2,5-醌、6-O-丁香酰基-8-O-乙酰基山栀苷甲酯、丹参新酮Ⅱ、降丹参酮、茵陈色原酮、依靛蓝酮等活性成分,作用于EGFR、MMP9、PTGS2、ESR1、PIK3CA、F2、PPARG、PTPN11等关键靶点,具体机制可能与HIF-1信号通路、C型凝集素受体信号通路、Toll样受体信号通路、肿瘤坏死因子信号通路、松弛素信号通路以及FoxO信号通路等有关。结论金丹健肝胶囊可通过多成分、多靶点和多通路方式抗肝纤维化。

Objective To elucidate the potential mechanism of Jindanjiangan Capsule in the treatment of liver fibrosis by network pharmacology and molecular docking.Methods Active ingredients and targets of Jindanjiangan Capsules were searched by Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP)and HERB databases,and the disease targets were screened by DisGeNET and Therapeutic Target Database(TTD)databases.The targets of the active ingredients of Jindanjiangan Capsule were matched with the disease targets,and the common targets were imported into the String database platform to construct a protein-protein interaction network(PPI)network.CytoNCA tool of Cytoscape 3.9.1 software was used for topological analysis to screen key targets.Traditional Chinese Medicine-Key Active Ingredients-Key Target Network was constructed by Cytoscape 3.9.1 Software.KEGG enrichment analysis of key targets was performed through the DAVID platform.The molecular docking of active ingredients and targets was performed to verify the above results using LeDock software.Results By screening,180 potential active ingredients and 1340 targets of Jindanjiangan Capsule and 1060 targets of liver fibrosis,and 273 common targets were obtained.29 key targets related to liver fibrosis were screened out by PPI network interaction,and verified by KEGG analysis and molecular docking.Jindanjiangan capsule acts on key targets such as EGFR,MMP9,PTGS2,ESR1,PIK3CA,F2,PPARG,and PTPN11 through active components such as isovitexin,quercetin 7-O-β-D-glucoside,(3S,6S)-3-(benzyl)-6-(4-hydroxybenzyl)piperazine-2,5-quinone,6-Osyringoyl-8-O-acetylshanzhiside methyl ester,tanshinone II,nortanshinone,capillaris chromone,and etanone.The specific mechanism may be related to HIF-1 signaling pathway,C-type lectin receptor signaling pathway,Toll-like receptor signaling pathway,tumor necrosis factor signaling pathway,relaxin signaling pathway,FoxO signaling pathway and so on.Conclusion Jindanjiangan capsule can effectively treat hepatic fibrosis through multi-component,multi-target and multi-pathway.