基于网络药理学与分子对接的半夏泻心汤治疗腹泻型肠易激综合征作用机制研究

Mechanism of Banxia Xiexin Decoction in Treating Diarrhea-predominant Irritable Bowel Syndrome Based on Network Pharmacology and Molecular Docking

目的:通过网络药理学及分子对接研究半夏泻心汤治疗腹泻型肠易激综合征(IBS-D)的分子作用机制。方法:从中药系统药理学数据库与分析平台(TCMSP)中检索半夏泻心汤主要的有效成分和靶标。在GeneCards、OMIM、DrugBank、PharmGKB数据库中寻找IBS-D的疾病效应靶点,并应用Cytoscape软件构建半夏泻心汤药物-活性成分-靶点网络。对药物成分靶点与疾病靶点取交集,利用STRING数据库建立蛋白质的交互作用网络,以解析蛋白质-蛋白质相互作用(PPI)关系。对核心靶点展开基因本体(GO)功能和京都基因与基因组百科全书(KEGG)通路富集分析。采用AutoDock软件对主要的活性成分与核心蛋白进行分子对接,以评价其结合能力。结果:半夏泻心汤中含有143个活性化合物;化合物靶点与IBS-D疾病靶点有58个交集靶点;通过药物-活性成分-靶点网络推测半夏泻心汤治疗IBS-D的关键成分有槲皮素、汉黄芩素、山柰酚、金合欢素、甘草查耳酮A、黄芩素等,PPI网络中核心靶点为原癌基因蛋白Jun(JUN)、FOS、核转录因子-κB(NF-κB)p65(RELA)、蛋白激酶B1(Akt1)、雌激素受体1(ESR1)、细胞周期蛋白D1(CCND1)、MYC、缺氧诱导因子1-α(HIF1A)、细胞周期素依赖激酶抑制因子1A(CDKN1A)、丝裂原活化蛋白激酶1(MAPK1)等。GO富集得到1615个条目,其中生物过程、细胞组分、分子功能分别获得1403、69、143条。KEGG通路富集得到181个通路,主要涉及白细胞介素-17(IL-17)、NF-κB、Toll样受体(TLR)、肿瘤坏死因子(TNF)等信号通路。分子对接结果显示,半夏泻心汤核心化合物与其治疗IBS-D的核心靶点均有较好的结合活性。结论:半夏泻心汤可通过槲皮素、汉黄芩素、山柰酚等主要活性成分作用于JUN、FOS、RELA等靶点,通过参与IL-17、NF-κB、TLR等信号通路有效治疗IBS-D。

Objective:To investigate the molecular mechanism of Banxia Xiexin Decoction intreating diarrheapredominant irritable bowel syndrome(IBS-D)by network pharmacology and molecular docking.Methods:The main active ingredients and targets of Banxia Xiexin Decoction were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP).The disease effect targets of IBS-D were searched in GeneCards,OMIM,DrugBank and PharmGKB databases,while Cytoscape software was used to construct the herb-active ingredienttarget network of Banxia Xiexin Decoction.After obtaining the intersection of drug ingredient targets and disease targets,the interaction network of proteins was established by STRING database to analyze the protein-protein interaction(PPI)relationship.Gene ontology(GO)function and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis were performed on the core targets.AutoDock software was used to perform molecular docking between the main active ingredients and the core proteins to evaluate their binding ability.Results:Banxia Xiexin Decoction contained 143 active compounds,while 58 intersection targets were detected between compound targets and IBS-D disease targets.It is speculated from the drug-active ingredient-target network that the key ingredients of Banxia Xiexin Decoction in the treatment of IBS-D were quercetin,wogonin,kaempferol,acacetin,licochalcone A,baicalein,etc.The core targets in the PPI network were the proto-oncogene protein jun(JUN),fos oncogene(FOS),nuclear transcription factor-κB p65(RELA),protein kinase B1(Akt1),estrogen receptor(ESR1),cyclin(CCND1),myc oncogene(MYC),hypoxia-inducible factor 1-alpha(HIF1A),cyclin-dependent kinase inhibitor 1A(CDKN1A),mitogen-activated protein kinase 1(MAPK1),etc.GO enrichment obtained 1615 items,including 1403,69 and 143 items in biological processes,cellular components and molecular functions,respectively.KEGG pathway enrichment obtained 181 pathways,mainly involving interleukin-17(IL-17),nuclear factor-κB(NF-κB),Toll-like receptor(TLR),tumor necrosis factor(TNF)and other signaling pathways.The results of molecular docking showed that the core compounds of Banxia Xiexin Decoction had good binding activity with their core targets for the treatment of IBS-D.Conclusion:Banxia Xiexin Decoction may act on JUN,FOS,RELA and other targets through quercetin,wogonin,kaempferol and other main active ingredients,thereby effectively treating IBS-D by participating in IL-17,NF-κB,TLR and other signaling pathways.