基于网络药理学和分子对接技术探讨雷公藤卵巢毒性的机制

Molecular mechanism of ovarian toxicity of Tripterygium wilfordii Hook.F.:a study based on network pharmacology and molecular docking

目的:通过网络药理学和分子对接技术探讨雷公藤卵巢毒性的作用机制。方法:通过中药系统药理数据库及分析平台(TCMSP)和比较毒理基因组学数据库(CTD)收集雷公藤的候选毒性化合物和靶点,从CTD中获得雷公藤潜在的卵巢毒性靶点,并利用STRING数据库对雷公藤卵巢毒性的靶点基因进行分析。用Cytoscape软件构建蛋白质-蛋白质相互作用(PPI)网络,用cytoHubba插件鉴定核心基因。此外,利用R软件对雷公藤卵巢毒性的靶点基因进行基因本体(GO)和京都基因与基因组百科全书(KEGG)富集分析。最后,使用Discovery Studio软件对核心毒性化合物和核心基因进行分子对接验证。结果:共获得9个雷公藤候选毒性化合物和56个潜在的卵巢毒性靶点。网络分析结果,雷公藤甲素、山柰酚和雷公藤红素是雷公藤的关键卵巢毒性化合物,核心卵巢毒性基因包括TP53、MYC、PTEN、MAPK3、MTOR、STAT3、EGFR、KRAS、CDH1和AKT1。GO和KEGG分析显示,雷公藤通过氧化应激、生殖系统发育和功能、细胞周期调节、对内源性激素和外源性刺激的反应、细胞凋亡调节、衰老等途径引起卵巢毒性。分子对接研究显示,雷公藤的3个关键卵巢毒性化合物可与10个核心基因的对接口袋相匹配。结论:雷公藤可能通过作用于10个核心基因和140条信号通路而导致卵巢毒性。

Objective:To explore the mechanism of ovarian toxicity ofTripterygium wilfordiiHook.F.(TwHF) by network pharmacology and molecular docking.Methods:The candidate toxic compounds and targets of TwHF were collected by the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP) and the Comparative Toxicogenomics Database(CTD).Then,the potential ovarian toxic targets were obtained from CTD,and the target genes of ovarian toxicity of TwHF were analyzed using the STRING database.The protein-protein interaction(PPI) network was established by Cytoscape and analyzed by the cytoHubba plug-in to identify hub genes.Additionally,the target genes of ovarian toxicity of TwHF were subjected to Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analyses by using the R software.Finally,Discovery Studio software was used for molecular docking verification of the core toxic compounds and the hub genes.Results:Nine candidate toxic compounds of TwHF and 56 potential ovarian toxic targets were identified in this study.Further network analysis showed that the core ovarian toxic compounds of TwHF were triptolide,kaempferol and tripterine,and the hub ovarian toxic genes includedTP53,MYC,PTEN,MAPK3,MTOR,STAT3,EGFR,KRAS,CDH1andAKT1.Besides,the GO and KEGG analysis indicated that TwHF caused ovarian toxicity through oxidative stress,reproductive system development and function,regulation of cell cycle,response to endogenous hormones and exogenous stimuli,apoptosis regulation and aging.The docking studies suggested that 3 core ovarian toxic compounds of TwHF were able to fit in the binding pocket of the 10 hub genes.Conclusion:TwHF may cause ovarian toxicity by acting on 10 hub genes and 140 signaling pathways.