targetTB: a target identification pipeline for Mycobacterium tuberculosis through an interactome, reactome and genome-scale structural analysis.
targetTB: a target identification pipeline for Mycobacterium tuberculosis through an interactome, reactome and genome-scale structural analysis.
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DOI：
10.1186/1752-0509-2-109
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发表时间：
2008-12-19
影响因子：
--
通讯作者：
Chandra N
中科院分区：
文献类型：
--
作者：
Raman K;Yeturu K;Chandra N
结核病仍然是最大的致命传染病之一，需要确定新的靶点和药物。识别和验证用于设计药物的适当靶点是药物发现的关键步骤，也是目前的主要瓶颈。目前临床上用于治疗许多疾病的大多数药物都是在不了解靶标的情况下设计的，这可能是因为以高通量方式识别此类靶标的标准方法实际上并不存在。利用现在可用的不同类型的“组学”数据，计算方法可以成为获得可能目标的短名单以进行进一步实验验证的强大手段。我们报告了针对结核分枝杆菌的综合计算机靶标识别流程 targetTB。该管道结合了蛋白质-蛋白质相互作用组的网络分析、反应组的通量平衡分析、实验得出的表型必要性数据、序列分析和靶向性的结构评估，使用我们最近开发的新算法。使用通量平衡分析和网络分析，首先鉴定出对结核分枝杆菌生存至关重要的蛋白质，然后与宿主进行比较基因组学，最后结合结合位点的新颖结构分析来评估蛋白质作为靶标的可行性。进一步的分析包括与表达数据的相关性、与肠道菌群蛋白的不相似性以及宿主中的“反靶标”，从而鉴定出 451 个高可信度靶标。通过对 228 个病原体基因组进行系统发育分析，进一步探索了入围目标，以确定广谱抗生素目标，同时还确定了结核病特异性目标。还分析了解决分枝杆菌持久性和耐药机制的目标。开发的管道为药物靶标识别提供了合理的方案，可能具有很高的成功率，预计将在药物发现过程中节省大量资金、资源和时间。与文献中先前建议的目标进行彻底比较，证明了我们研究中使用的综合方法的有用性，特别强调了系统级分析的重要性。该方法有潜力用作靶标识别和验证的通用策略，从而对大多数药物发现计划产生重大影响。
Tuberculosis still remains one of the largest killer infectious diseases, warranting the identification of newer targets and drugs. Identification and validation of appropriate targets for designing drugs are critical steps in drug discovery, which are at present major bottle-necks. A majority of drugs in current clinical use for many diseases have been designed without the knowledge of the targets, perhaps because standard methodologies to identify such targets in a high-throughput fashion do not really exist. With different kinds of 'omics' data that are now available, computational approaches can be powerful means of obtaining short-lists of possible targets for further experimental validation. We report a comprehensive in silico target identification pipeline, targetTB, for Mycobacterium tuberculosis. The pipeline incorporates a network analysis of the protein-protein interactome, a flux balance analysis of the reactome, experimentally derived phenotype essentiality data, sequence analyses and a structural assessment of targetability, using novel algorithms recently developed by us. Using flux balance analysis and network analysis, proteins critical for survival of M. tuberculosis are first identified, followed by comparative genomics with the host, finally incorporating a novel structural analysis of the binding sites to assess the feasibility of a protein as a target. Further analyses include correlation with expression data and non-similarity to gut flora proteins as well as 'anti-targets' in the host, leading to the identification of 451 high-confidence targets. Through phylogenetic profiling against 228 pathogen genomes, shortlisted targets have been further explored to identify broad-spectrum antibiotic targets, while also identifying those specific to tuberculosis. Targets that address mycobacterial persistence and drug resistance mechanisms are also analysed. The pipeline developed provides rational schema for drug target identification that are likely to have high rates of success, which is expected to save enormous amounts of money, resources and time in the drug discovery process. A thorough comparison with previously suggested targets in the literature demonstrates the usefulness of the integrated approach used in our study, highlighting the importance of systems-level analyses in particular. The method has the potential to be used as a general strategy for target identification and validation and hence significantly impact most drug discovery programmes.
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影响因子：
5.8
作者：
Date, SV;Marcotte, EM
通讯作者：
Marcotte, EM
影响因子：
3.1
作者：
Anishetty, S;Pulimi, M;Pennathur, G
通讯作者：
Pennathur, G
影响因子：
4.1
作者：
Bonora, Stefano;Di Perri, Giovanni
通讯作者：
Di Perri, Giovanni
影响因子：
2
作者：
Cornish-Bowden, A;Cárdenas, ML
通讯作者：
Cárdenas, ML
影响因子：
4.9
作者：
DENG, LY;MIKUSOVA, K;MCNEIL, MR
通讯作者：
MCNEIL, MR