基于大数据库寻找皮肤T细胞淋巴瘤潜在治疗药物

Searching for potential therapeutic drugs for cutaneous T-Cell lymphoma based on large database

目的:通过基于大数据库的生物信息学分析,寻找皮肤T细胞淋巴瘤(CTCL)治疗新方法。方法:通过重新质控并整合分析CTCL细胞经罗米地辛处理前、后的基因表达谱(GSE110248),筛选差异表达基因,通过DAVID数据库进行GO分析和KEGG信号通路富集;将差异基因导入Connectivity Map(CMap)数据库获得可对差异基因产生作用的药物分子,结合SubpathwayMiner软件包对CMap数据库中药物分子作用数据进行通路分析的结果筛选药物分子作用通路;利用STRING和Cytoscape 3.5.1构建蛋白-蛋白对接通路网络和药物-蛋白对接通路网络;利用Sybyl X-2.1.1进行分子对接验证候选药物与核心差异基因相互作用关系。结果:对GSE110248整合分析共获得630个差异表达基因,通过对差异基因富集后得到的12个CTCL相关KEGG通路和33个CMap数据库药物分子作用通路取交集,得到2条重叠通路和CMap数据库中14种作用于这2条通路的药物;通过绘制2个重叠通路中差异基因表达蛋白分子的PPI网络,确定WNT3为核心基因;最后,通过分子对接验证结果,筛选出茴香霉素、伊立替康、舒洛地尔、米安色林、罗格列酮、甲氟喹和屈氟尿苷为CTCL最具潜力的候选治疗药物。结论:生物信息学分析揭示CTCL药物治疗的分子机制,并为CTCL的抗肿瘤治疗提供新的思路。

Objective:In order to find a new method for treatment of cutaneous T-cell lymphoma(CTCL)through bioinformatics analysis based on large database.Methods:The differentially expressed genes were screened by analysis the gene expression profiles of CTCL cells before and after lomidisine treatment(GSE110248).GO analysis and KEGG signal pathway enrichment were conducted by DAVID database.The drug molecules that could affect the differential genes were obtained by imported the differential genes into the Connectivity Map(CMap)database,and the drug molecular action pathways were screened by analyzing the pathway of the drug molecular action data in the CMap database with SubpathwayMiner software package.The protein-protein docking pathway network and drug-protein docking pathway network were constructed by STRING and Cytoscape 3.5.1.Sybyl X-2.1.1 was used for molecular docking to verify the interaction relationship between candidate drugs and core differential genes.Results:630 differentially expressed genes were obtained by integrating and analyzing GSE110248.By intersection of 12 CTCL-related KEGG pathways that obtained after enrichment of differential genes and 33 drug molecular action pathways in CMap database,2 overlapping pathways and 14 drugs in CMap that act on these two pathways database were obtained.By drawing the differentially expressed protein molecules’PPI network in 2 overlapping pathways,WNT3 was defined as the core gene.Finally,through the results of molecular docking verification,the most potential therapeutic candidates’drugs for CTCL were selected as anisamycin,irinotecan,sulodil,mianserin,rosiglitazone,mefloquine,and triflurouridine.Conclusion:Bioinformatics analysis reveals the molecular mechanism of CTCL drug therapy and provides new ideas for anti-tumor therapy of CTCL.