基于网络药理学和分子对接探讨解毒通利方治疗肝纤维化的作用机制

Mechanism of Jiedu Tongli Decoction in treating hepatic fibrosis based on network pharmacology and molecular docking

目的采用网络药理学和分子对接的方法探讨解毒通利方治疗肝纤维化(HF)的可能作用机制。方法借助中药系统药理学数据库与分析平台(TCMSP)、本草组鉴(HERB)获得解毒通利方所有有效活性成分,通过TCMSP数据库将这些有效活性成分进行成分靶点预测,并与GeneCards数据库、PharmGkb数据库、TTD数据库、OMIM数据库和DrugBank数据库中HF疾病基因相关靶点使用R语言软件取交集,从而获得解毒通利方治疗HF的靶点;通过STRING绘制交集靶点的蛋白互作(PPI)网络,筛选核心蛋白;利用Cytoscape 3.8.0软件构建“中药—关键化合物—核心靶点”网络;运用R语言软件进行基因本体论(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,预测核心靶点的作用机制。最后,应用分子对接技术,将关键有效活性成分和PPI中核心蛋白进行分子对接。结果共筛选解毒通利方药物活性化合物172种,作用靶点4068个,构建PPI网络,运用“CytoNCA”插件筛选出IL6、AKT1、STAT1、RELA、MYC、FOS、STAT3、MAPK1、CCND1等19个核心蛋白。GO功能富集分析结果包括2612个生物过程,234种分子功能以及89种细胞组分,涉及氧化应激、化学应激、氧水平感知等过程。KEGG通路富集以病毒感染、炎症反应、细胞凋亡、脂质代谢、肿瘤等相关的信号通路为主。分子对接结果显示,关键靶点AKT1、STAT3和关键活性成分和柚皮素、甘草查尔酮结合能为负值,显示较好的结合能力。结论本研究揭示了解毒通利方中的化学成分与关键靶蛋白的结合通过调节多种生物学过程及信号通路治疗HF。

Objective To explore the molecular mechanism of Jiedu Tongli Decoction in treating hepatic fibrosis based on network pharmacology and molecular docking.Methods All active ingredients of Jiedu Tongli Decoction were obtained by using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP)and HERB(Ben Cao Zu Jian).The component targets of these active ingredients were predicted by TCMSP database,and their intersections with hepatic fibrosis gene-related targets in GeneCards database,PharmGkb database,TTD database,OMIM database,and DrugBank database by the R programming language.Then,the core targets of Jiedu Tongli Decoction in hepatic fibrosis were acquired.Protein interaction(PPI)networks of intersecting targets was drawn through STRING to screen core proteins.Cytoscape 3.8.0 was used to construct TCM-key compounds-core targets network.R language software was used to perform Gene Ontology(GO)functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis,to predict the mechanism of action of core targets.Finally,molecular docking technology was implemented to dock key active ingredients with PPI core protein.Results A total of 172 chemical components and 4068 target genes were screened from Jiedu Tongli Decoction.In PPI network,19 core proteins(IL6,AKT1,STAT1,RELA,MYC,FOS,STAT3,MAPK1,CCND1,etc.)were screened using"CytoNCA"plugin.GO functional enrichment analysis included 2612 biological process,234 molecular functions,89 cellular components,involving oxidative stress,chemical stress,oxygen levels,etc.The KEGG pathway enrichment analysis mainly included signal pathways related to viral infection,inflammatory response,cell apoptosis,lipid metabolism,tumors.Molecular docking results showed that the key targets AKT1,STAT3,and key active ingredients had negative binding energy to naringenin and licorice chalcone,showing good binding capacity.Conclusion The chemical components in Jiedu Tongli Decoction can treat HF by binding to key target proteins and regulating multiple biological processes and signaling pathways.