目的:基于药物分子分析对茯苓-白术-桂枝治疗类风湿关节炎的作用机制进行分析探究.方法:通过中药系统药理学数据库与分析平台(TCMSP)采集茯苓-白术-桂枝主要化学成分及作用靶点,通过GeneCards、在线人类孟德尔遗传数据库(OMIM)、DisGeNET三个疾病基因数据库收集类风湿关节炎相关靶点,取茯苓-白术-桂枝与类风湿关节炎相融合的作用靶点,在线绘制韦恩图.通过STRING数据库筛选共同作用靶点,导入Cytoscape 3.7.1软件构建药物-活性成分-核心靶点网络.基于DAVID网站对核心靶点进行基因本体论(GO)富集分析及京都基因与基因组百科全书(KEGG)通路富集分析,利用微生信在线绘图工具对GO、KEGG富集分析数据进行多维网络图形绘制.利用Schrodinger 2022.2软件中的Glide模块进行分子对接.结果:获得茯苓-白术-桂枝有效活性成分29个、靶点53个,类风湿关节炎相关疾病靶点3 394个,治疗类风湿关节炎的交集靶点有30个,其中β-谷甾醇、花旗松素、儿茶酚、豆甾醇等主要活性成分通过作用于前列腺素内过氧化物合成酶2(Prostaglandin-endoperoxide Synthase,PTGS2)、JUN原癌基因(Jun Proto-Oncogene,JUN)、半胱氨酸天冬氨酸蛋白酶 3(Cysteine Aspartate Proteinase 3,CASP3)、一氧化氮合酶3(Nitric Oxide Synthase 3,NOS3)、过氧化氢酶等关键靶点,参与肿瘤坏死因子(Tumor Necrosis Factor,TNF)信号通路、糖尿病并发症中的晚期糖基化终末产物(Advanced Glycation End Product,AGE)-晚期糖基化终末产物受体(Receptor of AGE,RAGE)信号通路、肿瘤抑制蛋白(Tumor Protein p5 3,TP53)等多种信号通路起到治疗类风湿关节炎的作用.分子对接结果显示β-谷甾醇、儿茶酚与CASP3有较稳定的结合力.结论:本研究证实茯苓-白术-桂枝通过多成分基于多靶点作用与多通路对类风湿关节炎起到治疗作用.
Action mechanism of tripartite medicines Fuling-Baizhu-Guizhi in treating rheumatoid arthritis based on network pharmacology and molecular docking technique
Objective:Based on drug molecular analysis,the action mechanism of tripartite medicines Fuling(Poria)-Baizhu(Rhizoma Atractylodis Macrocephalae)-Guizhi(Ramulus Cinnamomi)on rheumatoid arthritis was analyzed and explored.Methods:The main chemical constituents and action targets of tripartite medicines Fuling-Baizhu-Guizhi were collected from TCMSP,and the related action targets of rheumatoid arthritis were collected from GeneCards,OMIM,and DisGeNET disease gene databases.The common targets of tripartite medicines Fuling-Baizhu-Guizhi and rheumatoid arthritis were selected to draw Venn diagram online.Cytoscape 3.7.1 software was used to construct the drug-active ingredient-core target network after screening common acting targets in STRING database.The GO enrichment and KEGG pathway enrichment analyses were carried out for core targets based on David website,and multi-dimensional network graphics were drawn for GO enrichment and KEGG pathway enrichment analyses data by bioinformatics online mapping tool.Molecular docking was performed using the Glide module in Schrodinger 2022.2 software.Results:There were 29 effective compounds and 53 targets of tripartite medicines Fuling-Baizhu-Guizhi,3 394 targets of rheumatoid arthritis related diseases.There were 30 common targets for treating rheumatoid arthritis.Among them,beta-sitosterol,taxifolin,catechol,stigasterol and other main active components participated in regulating TNF signaling pathway,AGE-RAGE signaling pathway in diabetic complications,TP53 and other signaling pathways by acting on key targets such as PTGS2,JUN,CASP3,NOS3,and CAT to play a role in the treatment of rheumatoid arthritis.The molecular docking results showed that β-sitosterol and catechol had relatively stable binding force with CASP3.Conclusion:This study confirms that tripartite medicines Fuling-Baizhu-Guizhi have a therapeutic effect on rheumatoid arthritis through multi-components and multi-target action on multi-pathway.
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