目的采用生物信息学方法分析胞质分裂因子5(dedicator of cytokinesis 5 gene,DOCK5)在卵巢癌中的表达特征及临床意义。方法利用GEPIA、Kaplan-Meier Plotter等数据库比较DOCK5在卵巢癌与正常组织中的mRNA表达差异,并评估其与生存率和...目的采用生物信息学方法分析胞质分裂因子5(dedicator of cytokinesis 5 gene,DOCK5)在卵巢癌中的表达特征及临床意义。方法利用GEPIA、Kaplan-Meier Plotter等数据库比较DOCK5在卵巢癌与正常组织中的mRNA表达差异,并评估其与生存率和病理因素的关系。通过LinkedOmic数据库筛选与DOCK5相互作用的基因及蛋白,并进行基因本体(gene ontology,GO)和京都基因和基因组百科全书富集分析(Kyoto Encyclopedia of Genes and Genomes,KEGG)。基于癌症基因组图谱(the cancer genome atlas,TCGA)数据,探究DOCK5在卵巢癌免疫浸润中的作用,并结合单细胞数据集进行深度分析。同时,应用CellMiner数据库评估DOCK5的药物敏感度,并预测其潜在药物分子对接位点。结果与正常卵巢组织比较,DOCK5在卵巢癌组织中显著低表达(P<0.05),且其低表达与患者不良预后显著相关(P<0.05)。此外,DOCK5表达水平与患者年龄显著相关(P<0.05)。富集分析提示,DOCK5可能参与卵巢癌有关通路,其表达与卵巢癌中效应记忆T细胞(effector memory T cells,Tem)等免疫细胞的浸润水平呈显著正相关(P<0.001)。单细胞分析进一步显示,DOCK5表达与成纤维细胞通讯存在显著相关(P<0.01)。DOCK5低表达与3种药物的敏感度存在显著关联,且分子对接结果显示这些药物可与DOCK5蛋白形成稳定结合位点。结论DOCK5在卵巢癌中显著下调,其低表达与不良预后及免疫浸润密切相关。DOCK5可能成为潜在的免疫治疗靶点及药物敏感度预测生物学标志物。展开更多
Highly Pathogenic Avian Influenza（HPAI） H5N1 has attracted much attention as a potential pandemic virus in humans, which makes death inevitable in humans. Neuraminidase（NA） has an important role in viral replicati...Highly Pathogenic Avian Influenza（HPAI） H5N1 has attracted much attention as a potential pandemic virus in humans, which makes death inevitable in humans. Neuraminidase（NA） has an important role in viral replication. Thus, it is an attractive target when designing anti-influenza virus drug. However, evolving viruses cause some anti-viral drugs to be ineffective, as they show resistance to them. Selection of peptides as drug candidates is important for the peptide-receptor activity and good selectivity. Cyclic bonds in the peptide ligand design aim to improve the stability of the system and remove the obstacles in drug metabolism. The design is based on the polarity of the ligand and amino acid residues in the active site of NA. The results are 4200 cyclic pentapeptides as potential lead compounds. Docking simulations were conducted using MOE 2008.10 and were screened based on the value of the binding energy（？Gbinding）. ADME-Tox prediction assay was conducted on the selected ligands.Intra- and inter-molecular interactions, as well as changes in the form of bonds, were tested by molecular dynamics simulations at temperatures of 310 K and 312 K. The results of the docking simulations and toxicity prediction assay show that there are two ligands that have a residual interaction with the target protein： CLDRC and CIWRC. These two ligands have ？Gbindingvalues of –40.5854 and –39.9721 kcal/mol（1 kcal/mol = 4.18 k J/mol）. These ligands are prone to be mutagenic and carcinogenic, and they have a good oral bioavailability. The results show that the molecular dynamics of both ligand CLDRC and CIWRC are more feasible at the temperature of 312 K. At the end,both CIWRC and CLDRC ligands can be used as the drug candidates against H5N1 virus.展开更多
文摘目的采用生物信息学方法分析胞质分裂因子5(dedicator of cytokinesis 5 gene,DOCK5)在卵巢癌中的表达特征及临床意义。方法利用GEPIA、Kaplan-Meier Plotter等数据库比较DOCK5在卵巢癌与正常组织中的mRNA表达差异,并评估其与生存率和病理因素的关系。通过LinkedOmic数据库筛选与DOCK5相互作用的基因及蛋白,并进行基因本体(gene ontology,GO)和京都基因和基因组百科全书富集分析(Kyoto Encyclopedia of Genes and Genomes,KEGG)。基于癌症基因组图谱(the cancer genome atlas,TCGA)数据,探究DOCK5在卵巢癌免疫浸润中的作用,并结合单细胞数据集进行深度分析。同时,应用CellMiner数据库评估DOCK5的药物敏感度,并预测其潜在药物分子对接位点。结果与正常卵巢组织比较,DOCK5在卵巢癌组织中显著低表达(P<0.05),且其低表达与患者不良预后显著相关(P<0.05)。此外,DOCK5表达水平与患者年龄显著相关(P<0.05)。富集分析提示,DOCK5可能参与卵巢癌有关通路,其表达与卵巢癌中效应记忆T细胞(effector memory T cells,Tem)等免疫细胞的浸润水平呈显著正相关(P<0.001)。单细胞分析进一步显示,DOCK5表达与成纤维细胞通讯存在显著相关(P<0.01)。DOCK5低表达与3种药物的敏感度存在显著关联,且分子对接结果显示这些药物可与DOCK5蛋白形成稳定结合位点。结论DOCK5在卵巢癌中显著下调,其低表达与不良预后及免疫浸润密切相关。DOCK5可能成为潜在的免疫治疗靶点及药物敏感度预测生物学标志物。
基金Hibah PUPT BOPTN Ditjen Dikti 2015 No.0528/UN2.R12/HKP.05.00/2015,for supporting this research
文摘Highly Pathogenic Avian Influenza（HPAI） H5N1 has attracted much attention as a potential pandemic virus in humans, which makes death inevitable in humans. Neuraminidase（NA） has an important role in viral replication. Thus, it is an attractive target when designing anti-influenza virus drug. However, evolving viruses cause some anti-viral drugs to be ineffective, as they show resistance to them. Selection of peptides as drug candidates is important for the peptide-receptor activity and good selectivity. Cyclic bonds in the peptide ligand design aim to improve the stability of the system and remove the obstacles in drug metabolism. The design is based on the polarity of the ligand and amino acid residues in the active site of NA. The results are 4200 cyclic pentapeptides as potential lead compounds. Docking simulations were conducted using MOE 2008.10 and were screened based on the value of the binding energy（？Gbinding）. ADME-Tox prediction assay was conducted on the selected ligands.Intra- and inter-molecular interactions, as well as changes in the form of bonds, were tested by molecular dynamics simulations at temperatures of 310 K and 312 K. The results of the docking simulations and toxicity prediction assay show that there are two ligands that have a residual interaction with the target protein： CLDRC and CIWRC. These two ligands have ？Gbindingvalues of –40.5854 and –39.9721 kcal/mol（1 kcal/mol = 4.18 k J/mol）. These ligands are prone to be mutagenic and carcinogenic, and they have a good oral bioavailability. The results show that the molecular dynamics of both ligand CLDRC and CIWRC are more feasible at the temperature of 312 K. At the end,both CIWRC and CLDRC ligands can be used as the drug candidates against H5N1 virus.
