targetTB: a target identification pipeline for Mycobacterium tuberculosis through an interactome, reactome and genome-scale structural analysis.

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Raman K, Yeturu K, Chandra N

targetTB: a target identification pipeline for Mycobacterium tuberculosis through an interactome, reactome and genome-scale structural analysis.

BMC Syst Biol. 2008 Dec 19;2:109. doi: 10.1186/1752-0509-2-109.

PubMed ID
19099550 [ View in PubMed
]
Abstract

BACKGROUND: 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. RESULTS: 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. CONCLUSION: 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.

DrugBank Data that Cites this Article

Polypeptides
NameUniProt ID
Cyclopropane mycolic acid synthase MmaA2Q79FX6Details
Hydroxymycolate synthase MmaA4Q79FX8Details
Probable arabinosyltransferase AP9WNL9Details
Enoyl-[acyl-carrier-protein] reductase [NADH]P9WGR1Details
Catalase-peroxidaseP9WIE5Details
Probable arabinosyltransferase CP9WNL5Details
Cyclopropane mycolic acid synthase 2P9WPB5Details
Thymidylate kinaseP9WKE1Details
6,7-dimethyl-8-ribityllumazine synthaseP9WHE9Details
Pantothenate synthetaseP9WIL5Details
Diacylglycerol acyltransferase/mycolyltransferase Ag85CP9WQN9Details
Putative 4-hydroxy-4-methyl-2-oxoglutarate aldolaseP9WGY3Details
3-oxoacyl-[acyl-carrier-protein] synthase 3P9WNG3Details
2-isopropylmalate synthaseP9WQB3Details
3-dehydroquinate dehydrataseP9WPX7Details
Mycocyclosin synthaseP9WPP7Details
D-3-phosphoglycerate dehydrogenaseP9WNX3Details
Cyclopropane mycolic acid synthase 3P9WPB3Details
Group 1 truncated hemoglobin GlbNP9WN25Details
Mycothiol acetyltransferaseP9WJM7Details
NAD(P)H dehydrogenase (quinone)P9WHH7Details
dTDP-4-dehydrorhamnose 3,5-epimeraseP9WH11Details
Proteasome subunit alphaP9WHU1Details
Probable L-lysine-epsilon aminotransferaseP9WQ77Details
Peptide deformylaseP9WIJ3Details
Secreted chorismate mutaseP9WIB9Details
Arylamine N-acetyltransferaseP9WJI5Details
ATP synthase subunit cP9WPS1Details