基于数据挖掘和网络药理学研究中药复方治疗重症肌无力的用药规律及作用机制

Administration rule and mechanism of traditional Chinese medicine compound in the treatment of myasthenia gravis:a study based on data mining and network pharmacology

关键词:  数据挖掘  网络药理学  重症肌无力  用药规律  作用机制  中医药

Key words:  data mining  network pharmacology  myasthenia gravis  medication rule  mechanism of action  traditional Chinese medicine

摘要:

[目的] 基于国家专利、中国知网及万方数据库探究中药复方治疗重症肌无力的用药规律，同时分析核心药对的作用机制，以期为中药复方治疗重症肌无力提供理论依据。[方法] 检索国家知识产权局中国专利公布公告数据库、中国知网及万方数据库，获取中药复方治疗重症肌无力的处方数据，利用R语言、SPSS、IBMSPSSModeler软件对专利复方进行频数统计、关联规则分析及系统聚类分析，分析专利中药复方治疗重症肌无力的用药规律。基于网络药理学方法对筛选出的核心药对的潜在靶点及通路进行预测，构建“中药-成分-靶点”及蛋白质互作网络（PPI），利用Autodock进行分子对接预测。[结果] 数据挖掘共纳入中药复方151条，中药352味，其中高频中药共26味，关联规则分析共筛出核心药对76项，包括中药7味，聚类分析共得到7类，包括3个聚类方，3个聚类药对及1个单药，选取核心药物组合“柴胡-当归-黄芪-党参-白术-升麻”进行网络药理学分析，得到药物组合核心活性成分10个，包括槲皮素、木犀草素、山柰酚、7-甲氧基-2-甲基异黄酮、7-O-甲基异微凸剑叶莎醇、异鼠李素、甲氧异黄酮、β-谷甾醇、豆甾醇及毛蕊异黄酮，核心作用靶点14个，包括蛋白激酶B1（AKT1）、表皮生长因子受体（EGFR）、原癌基因FOS（FOS）、原癌基因JUN（JUN）、原癌基因MYC（MYC）、白细胞介素-6（IL-6）、肿瘤坏死因子（TNF）、胱天蛋白酶3（CASP3）、白细胞介素-1β（IL-1β）、C反应蛋白（CRP）、肿瘤抑制蛋白（TP53）、血管内皮生长因子A（VEGFA）、雌激素受体（ESR1）、酪氨酸激酶受体2（ERBB2），分子对接结果提示核心成分与核心靶点结合稳定，平均最低结合能为-6.23kcal/mol。[结论] 中药复方治疗重症肌无力用药多以补益虚损为法，辅以活血通经、舒筋通络等，其核心药物组合“柴胡-当归-黄芪-党参-白术-升麻”主要通过参与调节免疫，炎症反应等机制，作用于突触后膜等细胞成分，影响G蛋白偶联乙酰胆碱受体活性等分子功能发挥重症肌无力的治疗作用，并可能通过靶向EGFR治疗胸腺相关型重症肌无力，可为中药复方治疗重症肌无力的机制研究及临床用药提供参考。

Abstract:

[Objective] To explore the medication rules of traditional Chinese medicine (TCM) compound in the treatment of myasthenia gravis(MG) based on the national patent,CNKI and Wangfang Database,and to analyze the mechanism of action of the core drug pair,in order to provide a theoretical basis for the treatment of MG with traditional Chinese medicine compound. [Methods] The prescription data of the treatment of myasthenia gravis by TCM compound were retrieved from National Intellectual Property Administration's China Patent Announcement database,CNKI and Wanfang database. Frequency statistics,association rule analysis and systematic cluster analysis were performed on the patented compound by R language,SPSS and IBM SPSS Modeler software and analyzed the medication rules of the patented TCM compound in the treatment of MG. Based on the network pharmacology method,the potential targets and pathways of the selected core drug pair were predicted,and the "Chinese medicine-component-target" and PPI interaction network were constructed. Autodock was used for molecular docking prediction. [Results] Data mining included 151 TCM compounds,352 Chinese herbs, including 26 high-frequency Chinese herbs. Association rule analysis screened out 76 core drug pairs,including 7 Chinese herbs. Cluster analysis obtained 7 categories,including 3 cluster prescriptions,3 cluster drug pairs and 1 single herbs. The core drug combinations of Chaihu,Angelica sinensis,Astragalus membranaceus,Codonopsis radix,Atractylodes atractylodes atractylodes and Cimichoma were selected for network pharmacology analysis,and 10 core active ingredients,including quercetin,luteolin,kaeferol,7-methoxy-2-methyl isoflavone,7-O-methylisobionsatin,isorhamnetin,formononetin,beta-sitosterol,Stigmasterol and Calycosin were obtained. And 14 core targets were obtained as well,including AKT1,EGFR,FOS,JUN,MYC,IL6,TNF,CASP3,IL1B,CRP,TP53,VEGFA,ESR1,and ERBB2. The results of molecular docking showed that the core components had stable binding with the core targets,and the average minimum binding energy was -6.23 kcal/mol. [Conclusion] This study revealed that the treatment of myasthenia gravis with traditional Chinese medicine compound is mainly based on the method of tonifying deficiency and loss,and supplemented with activating blood circulation and channeling channels,relaxing tendons and collaterals,and so on. The main active ingredients of the core drug combination "Radix Bupleuri,Angelicae Sinensis Radix,Hedysarum Multijugum Maxim,Codonopsis radix,Atractylodes Macrocephala Koidz and Cimicifugae Rhizoma" plays a therapeutic role in myasthenia gravis mainly by acting on cell components such as the postsynaptic membrane,affecting molecular functions such as G protein coupled acetylcholine receptor activity via participating in the regulation of immunity,inflammation and other mechanisms,and possibly targeting EGFR to treat thymus related myasthenia gravis,and it can provide a reference for the mechanism research and clinical medication of traditional Chinese medicine compound in treating myasthenia gravis.