基于CMAP数据库和分子对接的子宫内膜癌潜在药物筛选

Screening of potential drugs for urerine corpus endometrial carcinoma based on CMAP database and molecular docking

目的基于关联性图谱(CMAP)数据库和分子对接筛选子宫内膜癌(UCEC)的潜在药物。方法采用癌症基因组图谱(TCGA)和基因型-组织表达研究项目(GTEx)数据库筛选UCEC的差异表达基因(DEGs);通过基因本体(GO)和京都基因与基因组百科全书(KEGG)通路富集分析,构建蛋白质-蛋白质相互作用网络和药物基因网络,预测相关靶点和通路,阐明UCEC的潜在分子机制;比较DEGs与CMAP数据库中的药物基因组表达谱,筛选出具有特异性的小分子化合物;验证UCEC相关蛋白和基因的表达并分析分子对接精度的准确性。结果共获得112个UCEC相关基因,其中上调基因48个,下调基因64个。GO和KEGG分析表明,112个UCEC相关基因主要集中在血管平滑肌收缩、紧密连接、细胞黏附分子等通路。与CMAP数据库的DEGs比较得出,25种化合物可能与UCEC的治疗有关。比较E-钙粘蛋白(CDH1)活性中心配体与橘皮素、木犀草素的最佳构象发现,天然配体在三维X射线衍射图像中与蛋白质晶体具有相同的药物结合位置,且其大部分构象重叠。结论本研究通过CMAP数据库预测UCEC相关小分子药物,利用分子对接技术和生物信息学初步探索橘皮素和木犀草素治疗UCEC的可能性,为后续的体外和体内实验提供了新的方向。

Objective To screen potential drugs for uterine corpus endometrial carcinoma(UCEC)based on connectivity map(CMAP)database and molecular docking.Methods The differentially expressed genes(DEGs)in UCEC by using the cancer genome atlas(TCGA)and the genotype-tissue expression(GTEx)database was screened;through gene ontology(GO)and Kyoto encyclopedia of genes and genomes(KEGG)pathway enrichment analysis,protein-protein interaction network and drug gene network were constructed to predict related targets and pathways,and to elucidate the potential molecular mechanism of UCEC.The drug genome expression profiles in DEGs and CMAP databases were compared to screen out specific small molecule compounds.The expression of UCEC related proteins and genes were verified and the accuracy of molecular docking accuracy was analyzed.Results A total of 112 UCEC related genes were obtained,including 48 up-regulated genes and 64 down-regulated genes.GO and KEGG analysis showed that 112 UCEC related genes were mainly concentrated in vascular smooth muscle contraction,tight junction,cell adhesion molecules and other pathways.Compared with the DEGs in the CMAP database,25 compounds may be related to the treatment of UCEC.Comparing the optimal conformation of E-cadherin(CDH1)active center ligand with tangeretin and luteolin,it was found that the natural ligand had the same drug binding position with the protein crystal in the three-dimensional X-ray diffraction image,and most of its conformations overlapped.Conclusion This study predicts small molecule drugs related to UCEC through CMAP database,and explores the possibility of tangeretin and luteolin in the treatment of UCEC through molecular docking technology and bioinformatics,which provided a new direction for subsequent in vitro and in vivo experiments.