基于分子对接和网络药理学分析金银花-黄连治疗关节假体周围感染的作用及分子机制

Effect and molecular mechanism of Honeysuckle-Rhizoma coptidis in the treatment of periprosthetic joint infection based on molecular docking and network pharmacology

背景:有研究表明金银花、黄连中多种单体治疗关节假体周围感染有效,关于金银花、黄连单独作用的研究较多,但金银花-黄连的共同药理作用机制鲜有文献报道。目的:基于分子对接和网络药理学手段探究金银花-黄连治疗关节假体周围感染的潜在有效成分、靶点和作用机制。方法:通过传统中药系统药理学数据库和分析平台(TCMSP)筛选金银花、黄连的有效成分和靶点基因。使用人类基因数据库(GeneCards)和在线孟德尔遗传数据库(OMIM)获得关节假体周围感染靶点基因,取交集后获得金银花-黄连与关节假体周围感染的交集基因。通过STRING数据库构建靶点蛋白质之间相互作用(PPI)网络,利用Cytoscape 3.7.2软件中"Cyto NCA"插件对该PPI网络做拓扑分析和核心靶点筛选,再通过Cytoscape 3.7.2软件构建"中药-有效成分-交集靶点-疾病""有效成分-交集靶点"和"通路-富集基因"网络。利用DAVID在线工具进行交集靶点的基因本体论(GO)功能和京都基因与基因组百科全书(KEGG)通路富集分析,并通过分子对接验证有效成分与靶点亲和力。结果与结论:①通过数据库筛选获得金银花治疗关节假体周围感染的有效成分14个及对应靶点183个,黄连治疗关节假体周围感染的有效成分9个及对应靶点158个;②共获得关节假体周围感染相关基因286个,药物和疾病的交集基因37个,PPI网络筛选出白细胞介素6等17个核心基因;③GO功能富集显示,金银花-黄连治疗关节假体周围感染的生物功能共有59个,其中生物过程44个,细胞组分6个,分子功能9个;④KEGG通路富集共筛选出17条信号通路;⑤分子对接结果显示,槲皮素、木犀草素、山柰酚与白细胞介素6、基质金属蛋白酶9、白细胞介素1β具有良好的亲和力;⑥结果证实,金银花-黄连治疗关节假体周围感染的具体机制涉及槲皮素和木犀草素等多个有效化合物,南美锥虫病和肿瘤坏死因子信号通路等多个作用途径,白细胞介素6和前列腺素内过氧化物合酶2等多个靶点基因,这些化合物、靶点基因和途径可共同协调药物发挥治疗作用。此外,文章还发现了潜在有效成分槲皮素,为后续深入研究提供了新导向和新思路。

BACKGROUND:Studies have shown that various monomers of Honeysuckle and Rhizoma coptidis are effective in the treatment of periprosthetic joint infections.There are many studies on the individual effects of Honeysuckle and Rhizoma coptidis,but the common pharmacological mechanism of Honeysuckle and Rhizoma coptidis is rarely reported.OBJECTIVE:To explore the potential effective components,to rgets and action mechanisms of Honeysuckle-Rhizoma coptidis in the treatment of periprosthetic joint infection based on molecular docking network pharmacology.METHODS:The effective components and to rget genes of Honeysuckle and Rhizoma coptidis were screened by traditional Chinese medicine system pharmacology database and analysis platfo rm.The GeneCards and On-line Mendelian Inheritance in Man were used to obtain the to rgets for periprosthetic joint infection,The intersection of the two was taken to obtain the Honeysuckle,Rhizoma coptidis-periprosthetic joint infection disease intersection to rget,The protein-protein inte ra ction(PPI)network was constructed through the STRING database,and the"CytoNCA"plug-in in Cytoscape 3.7.2 software was used for topology analysis and core to rget screening of the PPI network.Afterwards,through Cytoscape 3.7.2 software,the network of"tra ditional Chinese medicineactive component-intersection to rget-disease","a ctive component-inte rsection to rget"and"pathway-enrichment gene"was constructed.DAVID was used to analyze the Gene Ontology(GO)function of the intersection to rget and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment.The affinity between the active components and the to rget was ve rified by molecular docking.RESULTS AND CONCLUSION:(1)Through data screening,14 effective components and 183 corresponding to rgets of Honeysuckle,9 effective components of Rhizoma coptidis and 158 corresponding to rgets were obtained for periprosthetic joint infection.(2)In addition,286 genes related to pe riprosthetic joint infection and 37 genes related to drug and disease were obtained.17 core genes(such as interleukin 6)were screened by PPI network.(3)GO function en richment showed that there were 59 biological functions of Honeysuckle-Rhizoma coptidis in the treatment of pe riprosthetic infection,including 44 biological processes,6 cellular components and 9 molecular functions.(4)A total of 17 signal pathways were screened by en richment of KEGG pathway.(5)The results of molecular docking showed that quercetin,luteolin,and kaempferol had good affinity with interleukin 6,matrix metalloproteinase 9 and interleukin 1β.(6)Results verified that Honeysuckle-Rhizoma coptidis is charactehzed by multiple effective compounds(such as quercetin and luteolin),multiple action pathways(such as Chagas disease and Toll-like receptor signaling pathway)and multiple to rget genes(such as prostaglandin-endoperoxide synthase 2 and interleukin 6)in the treatment of periprosthetic infection.These compounds,target genes and pathways can coordinate the therapeutic effect of drugs.In addition,quercetin was also found as a potential active ingredient,which provides a new direction and new idea for further research.