Potential drug targets in Mycobacterium tuberculosis through metabolic pathway analysis
Potential drug targets in Mycobacterium tuberculosis through metabolic pathway analysis
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DOI：
10.1016/j.compbiolchem.2005.07.001
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发表时间：
2005-10-01
影响因子：
3.1
通讯作者：
Pennathur, G
中科院分区：
文献类型：
--
作者：
Anishetty, S;Pulimi, M;Pennathur, G
结核分枝杆菌多药耐药变种的出现导致了对新型药物靶点的探索。我们对宿主智人和病原体M的代谢途径进行了计算机比较分析。结核酶的生化途径的M。将来自KEGG代谢途径数据库的结核分枝杆菌的蛋白质与来自宿主H. sapiens，通过对限制于H.智人亚群e值阈值截止值设定为0.005。酶，不显示任何的宿主蛋白质的相似性，低于这个阈值，被过滤掉作为潜在的药物靶标。我们已经确定了病原体M的六种独特途径。与宿主H.智人。这些途径的潜在药物靶点可能有助于发现广谱药物。还从与脂质代谢、碳水化合物代谢、氨基酸代谢、能量代谢、维生素和辅因子生物合成途径以及核苷酸代谢相关的途径中确定了潜在的药物靶点。在从这些途径中确定的185个不同靶点中，许多处于结核病结构基因组学联盟的不同进展阶段。作为一个案例研究，我们利用WHAT IF软件建立了一个潜在药物靶点MurD连接酶的同源性模型。该模型可进一步用于与合适抑制剂的计算机对接研究。结核菌蛋白质组参与了病原菌的代谢、持久性、毒力和细胞壁生物合成等重要方面。这种通过可靠和常规的生物信息学方法对宿主和病原体代谢途径的系统评价可以扩展到临床感兴趣的其他病原体。(c)2005爱思唯尔有限公司保留所有权利。
The emergence of multidrug resistant varieties of Mycobacterium tuberculosis has led to a search for novel drug targets. We have performed an insilico comparative analysis of metabolic pathways of the host Homo sapiens and the pathogen M. tuberculosis. Enzymes from the biochemical pathways of M. tuberculosis from the KEGG metabolic pathway database were compared with proteins from the host H. sapiens, by performing a BLASTp search against the non-redundant database restricted to the H. sapiens subset. The e-value threshold cutoff was set to 0.005. Enzymes, which do not show similarity to any of the host proteins, below this threshold, were filtered out as potential drug targets. We have identified six pathways unique to the pathogen M. tuberculosis when compared to the host H. sapiens. Potential drug targets from these pathways could be useful for the discovery of broad spectrum drugs. Potential drug targets were also identified from pathways related to lipid metabolism, carbohydrate metabolism, amino acid metabolism, energy metabolism, vitamin and cofactor biosynthetic pathways and nucleotide metabolism. Of the 185 distinct targets identified from these pathways, many are in various stages of progress at the TB Structural Genomics Consortium. However, 67 of our targets are new and can be considered for rational drug design.As a case study, we have built a homology model of one of the potential drug targets MurD ligase using WHAT IF software. The model could be further explored for insilico docking studies with suitable inhibitors.The study was successful in listing out potential drug targets from the M. tuberculosis proteome involved in vital aspects of the pathogen's metabolism, persistence, virulence and cell wall biosynthesis. This systematic evaluation of metabolic pathways of host and pathogen through reliable and conventional bioinformatic methods can be extended to other pathogens of clinical interest. (c) 2005 Elsevier Ltd. All rights reserved.