应用生物信息学从铁死亡角度筛选治疗慢性肾脏病天然药物成分

Application of bioinformatics to screen natural drug components for treating chronic kidney disease from the perspective of ferroptosis

目的:应用生物信息学从铁死亡角度分析筛选得到治疗慢性肾脏病(CKD)的天然药物及其有效成分,为CKD的治疗开辟新途径。方法:在GEO数据库中检索与CKD相关的符合筛选条件的数据库,并利用R语言的limma包获得CKD的差异表达基因(DEGs)。在FerrDb平台收集与铁死亡相关基因,将铁死亡相关基因与上述DEGs的交集基因构建蛋白互作网络,并对该网络进行拓扑学性质分析。再通过clusterProfiler、pathview等R包对交集基因进行功能富集分析(GO及KEGG)。最后利用symMap平台定位天然药物,并通过TCMSP找到天然药物所对应的小分子化合物及其所对应靶点后进行分子对接分析。结果:GEO数据库筛选出GSE66494和GSE120683数据集,通过limma差异分析后得到1021个靶点。通过FerrDb平台收集得到与铁死亡相关靶点259个,取铁死亡与CKD差异表达共同靶点构建PPI网络与拓扑学性质分析可到关键靶点18个。GO及KEGG富集分析显示,CKD从铁死亡角度或与小分子分解代谢过程、哺乳动物雷帕霉素靶蛋白(mTOR)信号通路传导等相关。symMap及TCMSP数据库结果显示柠檬酸、香豆雌酚等天然小分子化合物与核心靶点能形成良好的分子对接。结论:通过生物信息学及分子对接操作,我们得到了来源于大黄等天然药物的柠檬酸、香豆雌酚或可能成为治疗CKD的关键候选药物,为CKD的新药研发及研究提供了新方向。

Objective:Bioinformatics was applied to analyze and screen the natural drugs and their effective components for the treatment of chronic kidney diseases(CKD)from the perspective of ferroptosis,opening up a new way for the treatment of CKD.Methodology:The databases related to CKD were searched in GEO database,and differential expression genes(DEGs)of CKD were obtained by using limmma package of R language.Genes related to ferroptosis were collected in FerrDb platform,and the protein interaction network was constructed by the intersection genes of ferroptosis related genes and the above DEGs,and the topology of the network was analyzed.Then,clusterProfiler,pathview and other R packages were used for functional enrichment analysis of intersected genes(GO,KEGG).Finally,symMap platform was used to locate natural drugs,and TCMSP was used to find the small molecule compounds corresponding to natural drugs and their corresponding targets for molecular docking analysis.Results:GEO database screened GSE66494 and GSE120683 data sets,and 1021 targets were obtained by limma difference analysis.A total of 259 targets related to ferroptosis were collected by FerrDb platform,and 18 key targets could be obtained by using the common targets of ferroptosis and differential expression of CKD to construct PPI network and topology analysis.GO and KEGG enrichment analysis showed that CKD was related to small molecule catabolic process and mTOR signaling pathway from the perspective of ferroptosis.SymMap and TCMSP database results showed that natural small molecule compounds such as Citric Acid and Coumestrol could form good molecular docking with the core target.Conclusion:Through bioinformatics and molecular docking,citric acid and Coumestrol derived from rhubarb and other natural drugs were obtained,which may become key candidate drugs for the treatment of CKD,providing a new direction for the research and development of new drugs for CKD.