基于网络药理学和分子对接技术探析鳖龙软肝汤治疗肝癌的机制

Mechanism of Bielong Ruangan decoction in treatment of liver cancer based on network pharmacology and molecular docking

目的运用网络药理学与分子对接技术探析鳖龙软肝汤治疗肝癌的关键靶点及作用机制。方法采用TCMSP、PubChem数据库、PharmMapper等数据库,检索并筛选鳖龙软肝汤化学成分及其相关靶点、肝癌疾病的靶点,构建"鳖龙软肝汤-中药-活性成分-预测靶点-疾病"网络图;采用String数据库做蛋白质相互作用(PPI)网络分析;采用WebGestalt数据库进行基因本体(GO)富集分析;采用KOBAS数据库进行京都基因与基因组百科全书(KEGG)富集分析;利用PyMOL和Auto DockVina等软件对鳖龙软肝汤活性成分和核心靶蛋白进行分子对接。结果鳖龙软肝汤有效成分67个,调控肝癌靶点154个和通路244条。网络药理学分析鳖龙软肝汤可能通过表皮生长因子受体(EGFR)、丝裂原活化蛋白激酶1(MAPK1)、雌激素受体1(ESR1)、MAPK8、丝氨酸苏氨酸蛋白激酶1(AKT1)、MAPK14、半胱氨酸蛋白酶3(CASP3)、细胞周期蛋白依赖性激酶2(CDK2)、骨形态发生蛋白2(BMP2)、醛糖还原酶(AKR1B1)等关键靶点发挥抗癌作用;KEGG富集分析显示,鳖龙软肝汤治疗肝癌涉及血管内皮生长因子(VEGF)信号通路、肿瘤坏死因子(TNF)信号通路、甲状腺激素信号通路、T细胞受体信号通路等通路的调控作用。分子对接结果显示各化合物与蛋白对接的结合能均<-5.6 kcal/mol,说明各化合物与各蛋白均结合较好。结论鳖龙软肝汤通过"多成分、多靶点、多途径"参与肝癌的治疗,主要通过调控肿瘤细胞的增殖与侵袭及肿瘤炎症微环境发挥抗癌作用。

Objective To explore the key targets and mechanism of Bielong Ruangan decoction in the treatment of liver cancer based on network pharmacology and molecular docking.Methods Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP)database,PubChem database and PharmMapper database were used to search and screen the chemical components and related targets of Bielong Ruangan decoction and the targets of liver cancer diseases.The network diagram of"Bielong Ruangan decoction-traditional Chinese medicine-active ingredient-predicted target-disease"was constructed;Protein-protein interaction(PPI)network were analyzed through String database;gene ontology(GO)enrichment analysis was performed through WebGestalt database;Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis was carried out through KEGG Orthology Based Annotation System(KOBAS)database;Molecular docking of the active components and core target proteins of Bielong Ruangan decoction was carried out by using PyMOL,Auto DockVina and other software.Results Bielong Ruangan decoction had 67 active components,154 liver cancer targets and 244 pathways.According to the analysis of network pharmacology,Bielong Ruangan decoction may play an anti-cancer role through key targets such as epidermal growth factor receptor(EGFR),mitogen activated protein kinase 1(MAPK1),estrogen receptor 1(ESR1),MAPK8,serine threonine protein kinase 1(AKT1),MAPK14,cysteine protease 3(CASP3),cyclin-dependent kinase 2(CDK2),bone morphogenetic protein 2(BMP2),aldose reductase(AKR1B1)and other key targets.KEGG enrichment analysis showed that the treatment of liver cancer by Bielong Ruangan decoction involved the regulation of vascular endothelial growth factor(VEGF)signaling pathway,tumor necrosis factor(TNF)signaling pathway,thyroid hormone signaling pathway,T cell receptor signaling pathway and other pathways.The results of molecular docking showed that the binding energy of all compounds to protein was less than-5.6 kcal/mol,indicating that each compound and each protein could bind well.Conclusions Bielong Ruangan decoction participates in the treatment of liver cancer through"multi-component,multi-target and multi-channel"ways,and plays an anti-cancer role mainly by regulating the proliferation and invasion of tumor cells and tumor inflammatory microenvironment.