基于网络药理学及分子对接探究木丹颗粒治疗糖尿病周围神经病变分子机制研究

A study on molecular mechanism of treating diabetic peripheral neuropathy with the Mudan granules based on network pharmacology and molecular docking

目的:基于药物分子分析对木丹颗粒防治糖尿病周围神经病变的作用机制进行分析探究。方法:通过中药药理数据库和分析平台(Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform,TCMSP)、化学专业数据库采集木丹颗粒中9味中药主要化学成分和作用的靶点,在GeneCards、OMIM、DrugBank三个疾病基因数据库中收集糖尿病周围神经病变相关靶点。取木丹颗粒与糖尿病周围神经病变相融合的作用靶点在线绘制韦恩图。通过在STRING数据库对共同作用靶点进行筛选,进而导入Cytoscape软件构建药物-活性成分-核心靶点网络。基于Metascape网站对核心靶点进行基因本体(Gene Ontology,GO)、京都基因和基因组数据库(Kyoto Encyclopedia of Genes and Genomes,KEGG)富集分析,利用微生信在线绘图对GO、KEGG富集分析数据进行多维网络绘图。结果:得到木丹颗粒治疗糖尿病周围神经病变的有效化合物成分198个、靶点282个,糖尿病周围神经病变相关疾病靶点2723个,木丹颗粒治疗糖尿病周围神经病变靶点共157个,其中β-谷甾醇(betasitostero)、豆甾醇(Stigmasterol)、槲皮苷(quercetin)、山柰酚(kaempferol)、木樨草素(luteolin)、芒柄花黄素(formononetin)、毛蕊异黄酮(Calycosin)等7种活性成分通过作用于TP53、肿瘤坏死因子(Tumor Necrosis Factor,TNF)、RELA原癌基因(RELA Proto-Oncogene,RELA)、转录因子活化蛋白-1(JUN)、丝裂原活化蛋白激酶1(Mitogen-activated Protein Kinase 1,MAPK1)、丝氨酸/苏氨酸蛋白激酶1(AKT Serine/Threonine Kinase 1,AKT1)等关键靶点,参与Pathways in cancer信号通路、AGE-RAGE信号通路、NF-κB信号通路,Dopaminergic synapse等多种信号通路起到治疗糖尿病周围神经病变的作用。分子对接结果显示MAPK1、AKT1与quercetin、kaempferol有较稳定的结合力。结论:本研究证实木丹颗粒是通过多成分基于多靶点作用于多通路对糖尿病周围神经病变起到治疗作用。

Objective:Based on drug molecular analysis,the mechanism of action of the Mudan granules(木丹颗粒)in the prevention and treatment of diabetic peripheral neuropathy was analyzed and explored.Methods:The main chemical components and action targets of nine TCM medicines in the Mudan granules were collected by TCMSP and chemical data database,and the related targets of diabetic peripheral neuropathy were collected from Genecards,OMIM and DrugBank.Venn diagrams was drawn online at the target fusion of the Mudan granules and DPN.The co-acting targets were screened in the STRING database,and then the Cytoscape software was imported to construct drug-active component-core target network.Go and KEGG enrichment analysis of core targets was carried out based on Metascape website,and online mapping of GO and KEGG enrichment analysis data was mostly carried out by bioinformaties.Results:198 effective compound components and 282 targets of the Mudan granules for the treatment of diabetic peripheral neuropathy were obtained,2723 targets of DPN-related diseases,and 157 targets of the Mudan granules for the treatment of DPN.Among them,seven active components,beta-sitostero,Stigmasterol,quercetin,luteolin kaempferol,luteolin,formononetin,Calycosin act on TP53,TNF,RELA(NF-κB p65),JUN,MAPK1,AKT1 and other key targets.Dopaminergic synapse plays a therapeutic role in DPN by participating in pathways such as pathways in cancer,NF-κB and AGE-RAGE.Molecular docking results showed that MAPK1 and AKT1 had stable binding force with quercetin and kaempferol.Conclusion:This study confirms that the Mudan granules have therapeutic effect on DPN through multicomponent,multi-target and multi-channel action.