Abstract
Multi drug resistance capacity for Mycobacterium leprae (MDR-Mle) demands the profound need for developing new anti-leprosy drugs. Since most of the drugs target a single enzyme, mutation in the active site renders the antibiotic ineffective. However, structural and mechanistic information on essential bacterial enzymes in a pathway could lead to the development of antibiotics that targets multiple enzymes. Peptidoglycan is an important component of the cell wall of M. leprae. The biosynthesis of bacterial peptidoglycan represents important targets for the development of new antibacterial drugs. Biosynthesis of peptidoglycan is a multi-step process that involves four key Mur ligase enzymes: MurC (EC:6.3.2.8), MurD (EC:6.3.2.9), MurE (EC:6.3.2.13) and MurF (EC:6.3.2.10). Hence in our work, we modeled the three-dimensional structure of the above Mur ligases using homology modeling method and analyzed its common binding features. The residues playing an important role in the catalytic activity of each of the Mur enzymes were predicted by docking these Mur ligases with their substrates and ATP. The conserved sequence motifs significant for ATP binding were predicted as the probable residues for structure based drug designing. Overall, the study was successful in listing significant and common binding residues of Mur enzymes in peptidoglycan pathway for multi targeted therapy.
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References
(2000) Leprosy-global situation. Wkly Epidemiol Rec 75:226–231
Levy L, Shepard CC, Fasal P (1976) The bactericidal effect of rifampicin on M. leprae in man: a) single doses of 600, 900 and 1200mg; and b) daily doses of 300mg. Int J Lepr Other Mycobact Dis 44:183–187
(1994) Chemotherapy of leprosy. Report of a WHO study group. World Health Organ Tech Rep Ser 847:1–24
Norman G, Joseph G, Ebenezer G, Rao SP, Job CK (2003) Secondary rifampin resistance following multi-drug therapy—a case report. Int J Lepr Other Mycobact Dis 71:18–21
Guelpa-Lauras CC, Grosset JH, Constant-Desportes M, Brucker G (1984) Nine cases of rifampin-resistant leprosy. Int J Lepr Other Mycobact Dis 52:101–102
Ji BH (1985) Drug resistance in leprosy—a review. Lepr Rev 56:265–278
Ji B (2002) Rifampicin-resistant leprosy: a review and a research proposal of a pilot study. Lepr Rev 73:2–8
Livermore DM (2003) Bacterial resistance: origins, epidemiology, and impact. Clin Infect Dis 36:S11–S23
Brennan PJ (2003) Structure, function and biogenesis of the cell wall of Mycobacterium tuberculosis. Tuberc Edinb 83:91–97
Draper P, Kandler O, Darbre A (1987) Peptidoglycan and arabinogalactan of Mycobacterium leprae. J Gen Microbiol 133:1187–1194
Barreteau H, Kovac A, Boniface A, Sova M, Gobec S, Blanot D (2008) Cytoplasmic steps of peptidoglycan biosynthesis. FEMS Microbiol Rev 32:168–207
Mahapatra S, Crick DC, Brennan PJ (2000) Comparison of the UDP-N-acetylmuramate: L-alanine ligase enzymes from Mycobacterium tuberculosis and Mycobacterium leprae. J Bacteriol 182:6827–6830
Shanmugam A, Natarajan J (2010) Computational genome analyses of metabolic enzymes in Mycobacterium leprae for drug target identification. Bioinformation 4:392–395
Anuradha CM, Mulakayala C, Babajan B, Naveen M, Rajasekhar C, Kumar CS (2009) Probing ligand binding modes of mycobacterium tuberculosis murc ligase by molecular modeling, dynamics simulation and docking. J Mol Model. doi:10.1007/s00894–009–0521–2
Sink R, Kovac A, Tomasić T, Rupnik V, Boniface A, Bostock J, Chopra I, Blanot D, Masic LP, Gobec S, Zega A (2008) Synthesis and biological evaluation of N-acylhydrazones as inhibitors of MurC and MurD ligases. Chem Med Chem 3:1362–1370
Perdih A, Kovac A, Wolber G, Blanot D, Gobec S, Solmajer T (2009) Discovery of novel benzene 1,3-dicarboxylic acid inhibitors of bacterial MurD and MurE ligases by structure-based virtual screening approach. Bioorg Med Chem Lett 19:2668–2673
Mansour TS, Caufield CE, Rasmussen B, Chopra R, Krishnamurthy G, Morris KM, Svenson K, Bard J, Smeltzer C, Naughton S, Antane S, Yang Y, Severin A, Quagliato D, Petersen PJ, Singh G (2007) Naphthyl tetronic acids as multi-target inhibitors of bacterial peptidoglycan biosynthesis. Chem Med Chem 2:1414–1417
Tomasić T, Zidar N, Kovac A, Turk S, Simcic M, Blanot D, Müller-Premru M, Filipic M, Grdadolnik SG, Zega A, Anderluh M, Gobec S, Kikelj D, Peterlin Masic L (2010) 5–Benzylidenethiazolidin–4–ones as multitarget inhibitors of bacterial Mur ligases. Chem Med Chem 5:286–295
Sova M, Kovac A, Turk S, Hrast M, Blanot D, Gobec S (2009) Phosphorylated hydroxyethylamines as novel inhibitors of the bacterial cell wall biosynthesis enzymes MurC to MurF. Bioorg Chem 37:217–222
Shanmugam A, Natarajan J (2011) Comparative modeling of UDP-N-acetylmuramoyl–glycyl–D-glutamate–2, 6–diaminopimelate ligase from Mycobacterium leprae and analysis of its binding features through molecular docking studies. J Mol Model. doi:10.1007/s00894–011–1039–y
Altschul SF, Madden TL, Schäffer AA, Zhang J, Zhang Z, Miller W, Lipman DJ (1997) Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res 25:3389–3402
Bernstein FC, Koetzle TF, Williams GJ, Meyer EF Jr, Brice MD, Rogers JR, Kennard O, Shimanouchi T, Tasumi M (1978) The protein data bank: a computer-based archival file for macromolecular structures. Arch Biochem Biophys 185:584–591
Larkin MA, Blackshields G, Brown NP, Chenna R, McGettigan PA, McWilliam H, Valentin F, Wallace IM, Wilm A, Lopez R, Thompson JD, Gibson TJ, Higgins DG (2007) ClustalW and ClustalX version 2.0. Bioinformatics 23:2947–2948
Sali A, Blundell TL (1993) Comparative protein modelling by satisfaction of spatial restraints. J Mol Biol 234:779–815
Laskowski RA, MacArthur MW, Moss DS, Thornton JM (1993) PROCHECK - a program to check the stereochemical quality of protein structures. J Appl Cryst 26:283–291
Maiti R, Van Domselaar GH, Zhang H, Wishart DS (2004) SuperPose: a simple server for sophisticated structural superposition. Nucleic Acids Res 32:W590–W594
Wishart DS, Knox C, Guo AC, Shrivastava S, Hassanali M, Stothard P, Chang Z, Woolsey J (2006) DrugBank: a comprehensive resource for in silico drug discovery and exploration. Nucleic Acids Res 34:D668–D672
ACD/ChemSketch Freeware, version 10.00, Advanced Chemistry Development, Inc., Toronto, ON, Canada, www.acdlabs.com
Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ (2009) AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem 30:2785–2791
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Shanmugam, A., Natarajan, J. Homology modeling and docking analyses of M. leprae Mur ligases reveals the common binding residues for structure based drug designing to eradicate leprosy. J Mol Model 18, 2659–2672 (2012). https://doi.org/10.1007/s00894-011-1285-z
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DOI: https://doi.org/10.1007/s00894-011-1285-z