基于网络药理学及分子对接技术探究三棱-莪术配伍在卵巢癌辅助治疗中的作用机制

Study on the Mechanism of Sanleng-Ezhu in the Adjuvant Treatment of Ovarian Cancer Based on Network Pharmacology and Molecular Docking

目的:基于网络药理学及分子对接技术,探究三棱-莪术药对在辅助治疗卵巢癌中的作用机制。方法:活性成分及其作用靶点收集自中药系统药理学分析平台,卵巢癌相关靶点收集自Genecard数据库。上述靶点取交集后,结合STRING数据库及Cytoscape软件构建PPI网络。应用R及Cytoscape软件整合构建中药-活性成分-疾病-靶点网络。同时,应用R软件进行基因本体论(gene ontology,GO)功能富集、京都基因与基因组百科全书(kyoto encyclopedia of genes and genomes,KEGG)通路富集,并通过Cytoscape/CluGO进行KEGG通路聚类分析。综合分析各网络,获取关键靶点及其对应活性成分后应用Autodock vina及Pymol等软件进行分子对接及可视化研究。结果:本研究在三棱-莪术药对中,共获得8个活性成分,164个作用靶点,Genecards数据库获得1540个符合条件的卵巢癌相关靶点。取交集获得27个三棱-莪术药对治疗卵巢癌的潜在靶点。分析PPI网络并获取关键靶点为CASP3、ESR1、JUN、PTGS2、AR、MAPK14、PGR、CASP8、CASP9、CAS及PPARG。GO及KEGG分析表明相关作用机制可能涉及凋亡、白细胞介素17(interleukin-17,IL-17)信号通路、乙肝信号通路、雌激素信号通路、甲状腺激素信号通路,卵巢类固醇等多条信号通路。分子对接表明核心成分芒柄花黄素、β-谷甾醇、常春藤皂苷元与关键靶点结合性良好,其中各活性成分与PTGS2结合最佳,结合能均小于-9.0 kcal/mol。结论:该研究初步揭示了三棱-莪术药对治疗卵巢癌的药理机制,这为后期探究该药对及其所在复方治疗卵巢癌提供了较为系统的依据。

Objective:To survey the mechanism of Sanleng-Ezhu in the adjuvant treatment of ovarian cancer based on network pharmacology and molecular docking.Methods:Active compounds and their potential targets were collected from TCMSP database,ovarian cancer(OC)related targets were obtained from Genecard database.After intersecting the targets mentioned above,PPI network was constructed by combining STRING database and Cytoscape software.R and Cytoscape software were used to construct TCM-active compounds-disease-target network.Meanwhile,R software was applied to perform GO enrichment and KEGG pathway enrichment,Cytoscape software/CluGO was used to carry out cluster analysis of KEGG pathway.Comprehensive analysis of all the network obtained the key targets and the corresponding active ingredients,Autodock vina and Pymol were exploited to conduct molecular docking and visualization study.Results:In the drug pair,eight active ingredients and 164 targets were obtained in the study,1540 OC related targets in line with the requirements were gained from Genecards database.27 potential targets of the drug pair for the treatment of ovarian cancer were obtained after intersection.The key targets obtained by analyzing PPI network were CASP3,ESR1,JUN,PTGS2,AR,MAPK14,PGR,CASP8,CASP9,CAS and PPARG.GO and KEGG analysis displayed that the relevant mechanism may involve apoptosis,IL-17 signaling pathway,hepatitis B signaling pathway,estrogen signaling pathway,thyroid hormone signaling pathway,ovarian steroids.Molecular docking indicated that the core components formononetin,β-sitosterol and hederagenin had good binding with key targets,among them,different active ingredients showed the best binding with PTGS2,and binding energy was less than-9.0 kcal/mol.Conclusion:The current study has preliminarily revealed the pharmacological mechanism of the treatment of ovarian cancer by Sanleng-Ezhu,which could provide a systematic basis for further exploration of the couplet medicine and its compounds in the treatment of the disease.