targetTB: a target identification pipeline for Mycobacterium tuberculosis through an interactome, reactome and genome-scale structural analysis.
Article Details
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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
Name UniProt ID Cyclopropane mycolic acid synthase MmaA2 Q79FX6 Details Hydroxymycolate synthase MmaA4 Q79FX8 Details Probable arabinosyltransferase A P9WNL9 Details Enoyl-[acyl-carrier-protein] reductase [NADH] P9WGR1 Details Catalase-peroxidase P9WIE5 Details Probable arabinosyltransferase C P9WNL5 Details Cyclopropane mycolic acid synthase 2 P9WPB5 Details Thymidylate kinase P9WKE1 Details 6,7-dimethyl-8-ribityllumazine synthase P9WHE9 Details Pantothenate synthetase P9WIL5 Details Diacylglycerol acyltransferase/mycolyltransferase Ag85C P9WQN9 Details Putative 4-hydroxy-4-methyl-2-oxoglutarate aldolase P9WGY3 Details 3-oxoacyl-[acyl-carrier-protein] synthase 3 P9WNG3 Details 2-isopropylmalate synthase P9WQB3 Details 3-dehydroquinate dehydratase P9WPX7 Details Mycocyclosin synthase P9WPP7 Details D-3-phosphoglycerate dehydrogenase P9WNX3 Details Cyclopropane mycolic acid synthase 3 P9WPB3 Details Group 1 truncated hemoglobin GlbN P9WN25 Details Mycothiol acetyltransferase P9WJM7 Details NAD(P)H dehydrogenase (quinone) P9WHH7 Details dTDP-4-dehydrorhamnose 3,5-epimerase P9WH11 Details Proteasome subunit alpha P9WHU1 Details Probable L-lysine-epsilon aminotransferase P9WQ77 Details Peptide deformylase P9WIJ3 Details Secreted chorismate mutase P9WIB9 Details Arylamine N-acetyltransferase P9WJI5 Details ATP synthase subunit c P9WPS1 Details