An in Silico Approach for Prioritizing Drug Targets in Metabolic Pathway of Mycobacterium Tuberculosis

There is an urgent need to develop novel Mycobacterium tuberculosis (Mtb) drugs that are active against drug resistant bacteria but, more importantly, kill persistent bacteria. Our study structured based on integrated analysis of metabolic pathways, small molecule screening and similarity Search in PubChem Database. Metabolic analysis approaches based on Unified weighted used for potent target selection. Our results suggest that pantothenate synthetase (panC) and and 3-methyl-2-oxobutanoate hydroxymethyl transferase (panB) as a appropriate drug targets. In our study, we used pantothenate synthetase because of existence inhibitors. We have reported the discovery of new antitubercular compounds through ligand based approaches using computational tools.




References:
[1] T. R. Ioerger, and J. C. Sacchettini, "Structural genomics approach to
drug discovery for Mycobacterium tuberculosis," CURR OPIN
MICROBIOL J., vol. 12, pp. 318-325, 2009.
[2] S. K. Kushwaha, and M. Shakya, "Protein interaction network analysis-
Approachforpotentialdrugtarget identification in Mycobacterium
tuberculosis,"-Theor. Biol. J., vol. 262, pp. 284-294, 2010.
[3] Y. Zhang, K. Post-Martens, and S. Denkin, "New drug candidates and
therapeutic targets for tuberculosis therapy," DDT J., vol. 11, no. 1/2,
pp. 21-27, Jan. 2006.
[4] G. J. Crowther et al. ,"Identification of Attractive Drug Targets in
Neglected-Disease Pathogens Using an In Silico Approach," PLoS Negl
Trop Dis J., vol. 4, no. 8, e804, Aug. 2010.
[5] S. Velaparthi et al., "5-tert-Butyl-N-pyrazol-4-yl-4,5,6,7-
tetrahydrobenzo[d]isoxazole-3-carboxamide derivatives as novel potent
inhibitors of Mycobacterium tuberculosis pantothenate pynthetase:
initiating a quest for new antitubercular drugs," J. Med. Chem, vol. 51,
pp. 1999-2002, Nov. 2007.
[6] Fabrizio Manetti et al., "Ligand-based virtual screening, parallel
solution-phase and microwave-assisted synthesis as tools to identify and
synthesize new inhibitors of Mycobacterium tuberculosis,"
ChemMedChem J., vol. 1, pp. 973 - 989, 2006.
[7] S. Ekins, J. S. Freundlich5, I. Choi, M. Sarker,-and C. Talcott, "
Computational databases, pathway and cheminformatics tools for
tuberculosis drug discovery," Trends Microbiol. J., vol.764, pp. 1-10,
2010.
[8] Q. Gao, K.E. Kripke, A.J. Saldanha, W. Yan, S. Holmes, P.M.
Small,"Gene expression diversity among Mycobacterium tuberculosis
clinical isolates," Microbiology J., vol. 151, pp.5-14, 2005.
[9] H. Rachman et al., "Unique transcriptome signature of Mycobacterium
tuberculosis in pulmonary tuberculosis," Infect. Immun. J., vol. 74, no.
2, pp. 1233-1242, 2006.
[10] H.I. Boshoff et al., "The transcriptional responses of-Mycobacterium
tuberculosis to inhibitors of metabolism: novel insights into drug
mechanisms of action," The Journal of Biological Chemistry J., vol. 279,
no. 38, pp. 40174-40184, 2004.
[11] S. Anishetty, M. Pulimi, and G. Pennathur., "Potential drug targets in
Mycobacterium tuberculosis through metabolic pathway analysis,"
Comput. Biol. Chem. J., vol. 29, no. 5, pp. 368-378, 2005.
[12] K. Raman, K. Yeturu, and N. Chandra., "targetTB: A target
identification pipeline for Mycobacterium tuberculosis through an
interactome, reactome and genome-scale structural analysis," BMC Syst.
Biol. J., vol. 2, no. 109, p. 21, 2008.
[13] S. Hasan, S. Daugelat, P.S. Srinivasa Rao, and M. Schreiber., "
Schreiber: Prioritizing genomic drug targets in pathogens: application to
Mycobacterium tuberculosis," PLoS Comput. Biol. J., vol. 2, no. 6, e61,
2006.
[14] V.K. Sambandamurthy et al., "A pantothenate auxotroph of
Mycobacterium tuberculosis is highly attenuated and protects mice
against tuberculosis," Nat. Med. J., vol. 8, no.10, pp. 1171-1174, 2002.
[15] M. Muddassar et al., " Identification of novel antitubercular compounds
through hybrid virtual screening approach," Bioorganic & Medicinal
Chemistry J., vol. 18, pp. 6914-6921, 2010.
[16] L. A. Basso et al., " The use of biodiversity as source of new chemical
entities against defined molecular targets for treatment of malaria,
tuberculosis, and T-cell mediated diseases - A Review," Mem Inst
Oswaldo Cruz, Rio de Janeiro, Vol. 100, no. 6, pp. 475-506, Oct. 2005.
[17] L. Respicio et al., " Characterizing septum inhibition in Mycobacterium
tuberculosis for novel drug discovery," Tuberculosis J., vol. 88, pp.420-
429, 2008.
[18] K. Duncan, "Identification and validation of novel drug targets in
tuberculosis," Curr. Pharm. J., vol. 10, PP. 3185-3194, Des. 2004.
[19] C.E. Barry, R.A. Slayden, A.E. Sampson, and R.E. Lee, " Use of
genomics and combinatorial chemistry in the development of new
antimycobacterial drugs," Biochem. Pharmacol. J., Vol. 59,-pp. 221-
231, 2000.