基于网络药理学与分子对接技术探讨四君子汤治疗IBS-D的分子靶点与作用机制研究

Molecular Target and Mechanism of Sijunzi Decoction in Treatment of IBS-D Based on Network Pharmacology and Molecular Docking

目的:基于网络药理学与分子对接技术探讨四君子汤治疗腹泻型肠易激综合征(IBS-D)的作用靶点及效应机制。方法:使用TCMSP平台与BATMAN数据库检索药物化学成分与作用靶点,GeneCards、OMIM、TTD、PharmGKB和DrugBank等数据库筛选疾病靶点,Uniprot数据库对靶点进行基因注释,Cytoscape 3.8.0构建药物-化合物-靶点网络,STRING构建PPI蛋白互作网络,根据拓扑参数筛选四君子汤治疗腹泻型肠易激综合征的核心靶点,通过Bioconductor在线软件进行基因组数据的高通量分析,进行GO生物功能注释和KEGG富集分析,后采用AutoDock软件对关键靶点与核心成分进行分子对接分析。结果:共筛选出四君子汤有效成分133个;预测药物与IBS-D疾病共有靶点196个;蛋白相互作用PPI网络筛选出JUN、STAT3、MAPK3等核心靶蛋白;借助分子对接技术,得到7-甲氧基-2-甲基异黄酮(7-Methoxy-2-methylisoflavone)、山柰酚(kaempferol)、木犀草素(luteolin)三个核心化合物,且关键靶蛋白与核心成分结合性能良好。KEGG富集分析结果表明,四君子汤干预IBS-D的信号通路主要与糖尿病并发症中的AGE-RAGE信号通路、前列腺癌通路、IL-17信号通路、脂质与动脉粥样硬化通路等途径相关。结论:四君子汤治疗IBS-D具有多成分、多靶点、多通路特点,其分子靶点及作用机制可能与调节肠道微生态、恢复肠道黏膜免疫功能、修复机械屏障损伤、抑制炎症反应激活、调控细胞的增殖与凋亡、肿瘤及糖脂代谢等途径有关。

Objective:To explore the target and mechanism of Sijunzi Decoction in the treatment of diarrheapredominant irritable bowel syndrome(IBS-D)based on network pharmacology and molecular docking technology.Methods:TCMSP platform and BATMAN database were used to retrieve chemical components and action targets;GeneCards,OMIM,TTD,PharmGKB and DrugBank databases were used to screen disease targets;Uniprot database was used for gene annotation of targets.Drug-compound target network was constructed with Cytoscape 3.8.0,and PPI protein interaction network was set up by STRING.Core targets of Sijunzi Decoction for the treatment of IBS-D were screened according to topological parameters.High-throughput analysis of genomic data was conducted through online software Bioconductor.GO biological function annotation and KEGG enrichment analysis were carried out,and then AutoDock software was used to conduct molecular docking analysis of key targets and core components.Results:A total of 133 active ingredients of Sijunzi Decoction were screened out.There were 196 predicted shared targets of drugs and IBS-D disease.Core target proteins,such as JUN,STAT3 and MAPK3,were screened by PPI network.Three core compounds,7-Methoxy-2-methyl isoflavone,kaempferol and luteolin,were obtained by molecular docking technology,and the binding properties of the key target proteins to the core components were good.KEGG enrichment analysis results showed that the signaling pathways of Sijunzi Decoction in the intervention of IBS-D were mainly related to the AGE-RAGE signaling pathway,prostate cancer signaling pathway,IL-17 signaling pathway,as well as lipid and atherosclerosis pathway.Conclusion:Sijunzi Decoction has the characteristics of multi-component,multi-target and multi-pathway in the treatment of IBS-D.Its molecular target and mechanism may be related to the regulation of intestinal microecology,recovery of intestinal mucosal immune function,repair of mechanical barrier damage,inhibition of inflammatory response activation,regulation of cell proliferation and apoptosis,tumor,as well as glucose and lipid metabolism.