基于网络药理学与分子对接探讨异莲心碱治疗人Burkitt淋巴瘤的作用机制

Mechanism of Isoliensinine in the Treatment of Burkitt Lymphoma Based on Network Pharmacology and Molecular Docking

目的 利用网络药理学联合分子对接的方法探讨异莲心碱治疗人Burkitt淋巴瘤的潜在分子机制。方法 将PharmMapper与Swiss TargetPrediction数据库用于预测异莲心碱的药物作用靶点,通过人类基因数据库GeneCards和在线人类孟德尔遗传数据库(OMIM)查询人Burkitt淋巴瘤的疾病靶点,整合两组数据绘制韦恩图、获得异莲心碱治疗人Burkitt淋巴瘤的靶标蛋白;利用蛋白相互作用数据库(STRING)及Cytoscape3.9.0软件构建靶标蛋白的蛋白相互作用网络(PPI);运用注释、可视化和集成发现的数据库(DAVID)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;采用AutoDock Vina软件将异莲心碱与预测的靶标蛋白进行分子对接验证,并利用Pymol软件进行可视化处理。结果 筛选获得异莲心碱作用于Burkitt淋巴瘤有49个预测靶点,PPI网络分析显示其核心靶点包括SRC、EGFR、MDM2、MTOR、PIK3CA、XIAP、RAF1、MAPK8/14等,GO富集分析显示其作用主要涉及细胞信号转导、凋亡调控、蛋白结合、蛋白激酶活性等生物学功能,KEGG富集分析显示ErbB、Ras、FoxO、PI3K/AKT、EGFR、MAPK等信号通路参与异莲心碱抗Burkitt淋巴瘤的调控过程,分子对接结果显示,异莲心碱与核心靶点SRC、EGFR、MDM2、MTOR、PIK3CA、XIAP、RAF1、MAPK8/14等均具有较好的结合活性。结论 异莲心碱可能是通过多靶点、多通路的方式发挥抗Burkitt淋巴瘤作用,受体酪氨酸激酶EGFR和非受体酪氨酸激酶SRC介导活化的PI3K-AKT-mTOR和RAS-RAF-MAPK信号通路极有可能在异莲心碱诱导Burkitt淋巴瘤凋亡过程发挥重要作用。

Objective To explore the potential molecular mechanism of isoliensinine in the treatment of human Burkitt lymphoma by network pharmacology combined with molecular docking. Methods Pharm Mapper and Swiss Target Prediction databases were used to predict the targets of isoliensinine. GeneCards and Online Mendelian Inheritance in Man(OMIM) databases were used for the query of the disease targets of human Burkitt lymphoma. The two sets of data were integrated to draw a Venn diagram to obtain the target protein of isoliensinine in treating human Burkitt lymphoma.The protein-protein interaction(PPI) network of the target protein was constructed by using the STRING database and Cytoscape3.9.0 software. Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analysis were carried out by using the databas for Annotation,Visualization and Integrated Discovery(DAVID). AutoDock Vina software was used to verify the molecular docking between isoliensinine and the predicted target protein. Pymol software was used for visualization. Results There were 49 predicted targets of isoliensinine in treating human Burkitt lymphoma,and PPI network analysis showed that the core targets included SRC,EGFR,MDM2,MTOR,PIK3CA,XIAP,RAF1,and MAPK8/14. GO enrichment analysis showed that the effects of isoliensinine on Burkitt lymphoma mainly involved in cell signal transduction,apoptosis regulation,protein binding,protein kinase activity,and other biological functions. And KEGG enrichment analysis showed that ErbB,Ras,FoxO,PI3K/AKT,EGFR,MAPK,and other signal pathways were involved in the regulation of isoliensinine against Burkitt lymphoma. The results of molecular docking showed that isoliensinine had a good binding activity with core targets such as SRC,EGFR,MDM2,MTOR,PIK3CA,XIAP,RAF1,and MAPK8/14. Conclusion The anti-Burkitt lymphoma effect of isoliensinine may be mediated by multiple targets and multiple pathways. The activation of PI3K-AKT-mTOR and RAS-RAF-MAPK signal pathways mediated by receptor tyrosine kinase EGFR and non-receptor tyrosine kinase SRC may play an important role in the apoptosis of Burkitt lymphoma induced by isoliensinine.