基于网络药理学和分子对接探讨四物汤抗乳腺癌的作用机制

Mechanism of Siwu Decoction on breast cancer based on network pharmacology and molecular docking

目的基于网络药理学和分子对接技术分析四物汤抗乳腺癌的作用机制。方法通过中药系统药理学数据库分析平台(TCMSP)获取熟地黄、白芍、川芎、当归的主要活性成分及其靶点,根据吸收、分布、代谢和排泄(absorption、distribution、metabolism and excretion,ADME)筛选中药活性组分;通过在线人类孟德尔遗传数据库(OMIM)、治疗靶标数据库(TTD)、Genecards和Drugbank数据库获取乳腺癌主要作用靶点;通过Venn Diagram得到四物汤与乳腺癌的共同靶点;利用BiosoGenet进行蛋白质-蛋白质相互作用(protein-protein interaction network,PPI)分析,构建PPI网络;采用Metascape平台分析“药物-成分-靶点”及其参与的生物过程及通路,采用Cytoscape 3.8.0软件构建“活性成分-疾病-通路”网络,并运用AutoDock及Pymol对关键靶点与相应活性成分进行分子对接验证。结果从四物汤中筛选得到40种活性成分及147个作用靶点,与1505个乳腺癌相关靶点取交集,得到61个共同靶点;四物汤抗乳腺癌的核心活性成分为山柰酚、β-谷甾醇、没食子酸、豆甾醇等,关键靶点为前列腺素G/H合酶2(prostaglandin G/H synthase 2,PTGS2)、雌激素受体(estrogen receptor1,ESR1)、RAC-α丝氨酸/苏氨酸-蛋白激酶(RAC-alpha serine/threonine-protein kinase,AKT1)等;四物汤抗乳腺癌的生物学通路众多,主要功能为调控细胞周期进程、血管生成、激素水平等。分子对接结果显示,筛选的主要活性成分与其对应靶蛋白均具有较好的结合活性。结论四物汤抗乳腺癌具有多成分、多靶点、多通路的特点,为其临床应用提供基础。

Objective To reveal the mechanism of Siwu Decoction(四物汤)on breast cancer based on network pharmacology and molecular docking.Methods Main chemical components and targets of Rehmanniae Radix Praeparata,Paeoniae Radix Alba,Chuanxiong Rhizoma and Angelicae Sinensis Radix were obtained from TCMSP database,and active components of Siwu Decoction were screened according to absorption,metabolism,distribution and excretion(ADME).Main targets of breast cancer were obtained from databases of Online Mendelian Inheritance in Man(OMIM),Therapeutic Target Database(TTD),Genecards and Drugbank.Common targets of Siwu Decoction and breast cancer were obtained by Venn Diagram,and BiosoGenet was used to analyze protein-protein interaction(PPI)and construct PPI network.Metascape platform was used to analyze“drug-component-target”and its involved biological processes and pathways,and then Cytoscape 3.8.0 software was used to construct a network of“active component-disease-pathway”.AutoDock and PyMol were used to conduct molecular docking verification of key targets and corresponding active ingredients.Results A total of 40 active ingredients were screened from Siwu Decoction,and 147 predicted targets were obtained;1505 main targets for breast cancer were obtained,61 common targets for active ingredients of Siwu Decoction and breast cancer were obtained.Core active ingredients from Siwu Decoction on breast cancer were kaempferol,β-sitosterol,gallic acid,stigmasterol and etc.Core targets were prostaglandin G/H synthase 2(PTGS2),estrogen receptor 1(ESR1),RAC-alpha serine/threonine-protein kinase(AKT1)and etc.Many biological pathways were involved in anti-breast cancer effect of Siwu Decoction with mainly function of regulating cell cycle process,angiogenesis and hormone levels.Molecular docking results showed that main active components had good binding activity with their corresponding target proteins.Conclusion Siwu Decoction has characteristics of multi-component,multi-target and multi-pathway on anti-breast cancer,which provides the basis for its clinical application.