基于网络药理学和分子对接探讨漏芦防治缺血性脑卒中的作用机制

Study on the Mechanism of Rhaponticum Uniflorum in the Prevention and Treatment of Ischemic Stroke Based on Network Pharmacology and Molecular Docking Analyses

目的基于网络药理学和分子对接技术探讨漏芦防治缺血性脑卒中的分子作用机制。方法通过中药系统药理学数据库和分析平台(TCMSP数据库)筛选并收集漏芦的有效活性成分,利用TCMSP、ETCM、Swiss Target Prediction、SymMap、CTD数据库检索并获取其对应的靶点。检索DisGeNET、TTD及Drugbank数据库中缺血性脑卒中相关的疾病靶点蛋白,再通过绘制韦恩图发现漏芦防治缺血性脑卒中的潜在作用靶标。药物-成分-疾病-靶点的互作网络可视化可通过Cytoscape软件构建,并根据网络拓扑参数进行关键靶点的筛选。利用DAVID数据库对上述关键靶点进行基因生物过程(GO)功能富集和信号通路(KEGG)富集分析。采用AutoDock软件对漏芦有效活性成分与其对应的核心靶点进行分子对接验证。结果共获取漏芦防治缺血性脑卒中的5种有效活性成分及118个潜在靶点,经Network Analyzer插件网络拓扑参数分析筛选后共获取44个关键靶点。GO富集分析共得到207个细胞生物过程条目、30个细胞组成条目以及35个分子功能条目;KEGG通路富集分析共获取76条信号通路。分子对接结果表明,漏芦有效活性成分与白蛋白(ALB)、白细胞介素-6(IL-6)、肿瘤坏死因子(TNF)、半胱氨酸蛋白酶-3(CASP3)及丝裂原活化蛋白激酶1(MAPK1)共5种核心靶点之间具有较好的结合活性。结论漏芦中的甘草素、β-谷甾醇、甘草苷等作用于ALB、IL-6、TNF、CASP3、MAPK1等靶点,调控TNF、低氧诱导因子、Toll样受体等信号通路发挥抑制炎症反应、抗氧化、调节免疫、促进血管新生和神经功能恢复等效应,从多方面起到防治缺血性脑卒中的作用。

Objective To explore the molecular mechanism of Rhaponticum uniflorum in the prevention and treatment of ischemic stroke based on network pharmacology and molecular docking technology.Methods The active components of Rhaponticum uniflorum were screened and collected by traditional Chinese medicine system pharmacology database and analysis platform(TCMSP database),and the corresponding targets were searched and obtained by TCMSP,ETCM,Swiss Target Prediction,SymMap,CTD database.The disease target proteins related to ischemic stroke were searched from DisGeNET,TTD,and Drugbank database,and then the potential targets for the prevention and treatment of ischemic stroke were found by drawing Venn diagram.The visualization of drug-components-disease-targets interaction network were constructed by Cytoscape software,and the key targets were screened according to the network topology parameters.The Gene Ontology(GO)function enrichment and Kyoto Encyclopedia of Genes and Genomes(KEGG)signal pathway enrichment analysis of the above key targets were carried out by DAVID database.Finally,the AutoDock software was used to verify the molecular docking between the active components of Rhaponticum uniflorum and its corresponding core targets.Results A total of 5 active components and 118 potential targets for the prevention and treatment of ischemic stroke were obtained,and 44 key targets were obtained after analysis and screening of topological parameters of"Network Analyzer"plug-in network.A total of 207 cell biological process items,30 cell composition items,and 35 molecular function items were obtained by GO enrichment analysis,and 76 signal pathways were obtained by KEGG pathway enrichment analysis.The results of molecular docking showed that the active components of Rhaponticum uniflorum had good binding activity with the core targets of albumin(ALB),interleukin-6(IL-6),tumor necrosis factor(TNF),cysteine proteinase-3(CASP3),and mitogen activated protein kinase-1(MAPK1).Conclusion Glycyrrhizin,β-sitosterol,glycyrrhizin,and other compounds in Rhaponticum uniflorum interact with ALB,IL-6,TNF,CASP3,and MAPK1,then further regulate TNF,HIF-1,and Toll-like receptor signal pathways to inhibit inflammation,antioxidation,regulate immunity,promote angiogenesis and neurological function recovery,and play its role in the prevention and treatment of ischemic stroke in many aspects.