title: Homology modeling and docking analyses of M. leprae Mur ligases reveals the common binding residues for structure based drug designing to eradicate leprosy.
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.
authors.affiliation: Department of Bioinformatics, VMKV Engineering College, Vinayaka Missions University, Salem, India.
authors.forename: Anusuya
authors.initials: A
authors.lastname: Shanmugam
authors.forename: Jeyakumar
authors.initials: J
authors.lastname: Natarajan
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry*; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry*; D020134:Catalytic Domain; D017124:Conserved Sequence; D015195:Drug Design; D018698:Glutamic Acid / Q000737:chemistry; D005998:Glycine / Q000737:chemistry; D006639:Histidine / Q000737:chemistry; D006801:Humans; D006860:Hydrogen Bonding; D007918:Leprosy / Q000382:microbiology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009166:Mycobacterium leprae / Q000201:enzymology*; D010453:Peptide Synthases / Q000737:chemistry*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D040681:Structural Homology, Protein; D013816:Thermodynamics
chemical_list: D001426:Bacterial Proteins; D018698:Glutamic Acid; D006639:Histidine; D000255:Adenosine Triphosphate; D010453:Peptide Synthases; C053379:UDP-N-acetylmuramoylalanine-D-glutamate ligase; D005998:Glycine
references.citation: Bioinformatics. 2007 Nov 1;23(21):2947-8
references.pmid: 17846036
references.citation: J Mol Model. 2012 Jan;18(1):115-25
references.pmid: 21491188
references.citation: ChemMedChem. 2007 Oct;2(10):1414-7
references.pmid: 17600795
references.citation: J Bacteriol. 2000 Dec;182(23):6827-30
references.pmid: 11073931
references.citation: Tuberculosis (Edinb). 2003;83(1-3):91-7
references.pmid: 12758196
references.citation: Nucleic Acids Res. 1997 Sep 1;25(17):3389-402
references.pmid: 9254694
references.citation: Nucleic Acids Res. 2004 Jul 1;32(Web Server issue):W590-4
references.pmid: 15215457
references.citation: ChemMedChem. 2010 Feb 1;5(2):286-95
references.pmid: 20024979
references.citation: Int J Lepr Other Mycobact Dis. 1976 Jan-Jun;44(1-2):183-7
references.pmid: 776856
references.citation: Clin Infect Dis. 2003 Jan 15;36(Suppl 1):S11-23
references.pmid: 12516026
references.citation: J Mol Biol. 1993 Dec 5;234(3):779-815
references.pmid: 8254673
references.citation: FEMS Microbiol Rev. 2008 Mar;32(2):168-207
references.pmid: 18266853
references.citation: J Mol Model. 2010 Jan;16(1):77-85
references.pmid: 19484275
references.citation: Lepr Rev. 2002 Mar;73(1):2-8
references.pmid: 11969122
references.citation: J Comput Chem. 2009 Dec;30(16):2785-91
references.pmid: 19399780
references.citation: ChemMedChem. 2008 Sep;3(9):1362-70
references.pmid: 18651694
references.citation: Bioinformation. 2010 Mar 31;4(9):392-5
references.pmid: 20975887
references.citation: Bioorg Med Chem Lett. 2009 May 15;19(10):2668-73
references.pmid: 19369074
references.citation: Bioorg Chem. 2009 Dec;37(6):217-22
references.pmid: 19804894
references.citation: Nucleic Acids Res. 2006 Jan 1;34(Database issue):D668-72
references.pmid: 16381955
references.citation: World Health Organ Tech Rep Ser. 1994;847:1-24
references.pmid: 7817604
references.citation: Int J Lepr Other Mycobact Dis. 2003 Mar;71(1):18-21
references.pmid: 12914130
references.citation: J Gen Microbiol. 1987 May;133(5):1187-94
references.pmid: 3309180
references.citation: Wkly Epidemiol Rec. 2000 Jul 14;75(28):226-31
references.pmid: 10920713
references.citation: Int J Lepr Other Mycobact Dis. 1984 Mar;52(1):101-2
references.pmid: 6538556
references.citation: Lepr Rev. 1985 Dec;56(4):265-78
references.pmid: 3908861
references.citation: Arch Biochem Biophys. 1978 Jan 30;185(2):584-91
references.pmid: 626512