title: Homology modeling and virtual screening approaches to identify potent inhibitors of VEB-1 β-lactamase.
abstract: BACKGROUND
  blaVEB-1 is an integron-located extended-spectrum β-lactamase gene initially detected in Escherichia coli and Pseudomonas aeruginosa strains from south-east Asia. Several recent studies have reported that VEB-1-positive strains are highly resistant to ceftazidime, cefotaxime and aztreonam antibiotics. One strategy to overcome resistance involves administering antibiotics together with β-lactamase inhibitors during the treatment of infectious diseases. During this study, four VEB-1 β-lactamase inhibitors were identified using computer-aided drug design.
  
  
  METHODS
  The SWISS-MODEL tool was utilized to generate three dimensional structures of VEB-1 β-lactamase, and the 3D model VEB-1 was verified using PROCHECK, ERRAT and VERIFY 3D programs. Virtual screening was performed by docking inhibitors obtained from the ZINC Database to the active site of the VEB-1 protein using AutoDock Vina software.
  
  
  CONCLUSIONS
  Homology modeling studies were performed to obtain a three-dimensional structure of VEB-1 β-lactamase. The generated model was validated, and virtual screening of a large chemical ligand library with docking simulations was performed using AutoDock software with the ZINC database. On the basis of the dock-score, four molecules were subjected to ADME/TOX analysis, with ZINC4085364 emerging as the most potent inhibitor of the VEB-1 β-lactamase.
authors.affiliation: Unité de Protéomie Fonctionnelle and Biopréservation Alimentaire, Institut Supérieur des Sciences Biologiques Appliquées de Tunis, Université Tunis El Manar, 09, Rue Docteur Zouheïr Safi - 1006, Tunis, Tunisia. messaoudiabdelmonemster@gmail.com
authors.forename: Abdelmonaem
authors.initials: A
authors.lastname: Messaoudi
authors.forename: Hatem
authors.initials: H
authors.lastname: Belguith
authors.forename: Jeannette
authors.initials: J
authors.lastname: Ben Hamida
mesh_terms: D000595:Amino Acid Sequence; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology; D029968:Escherichia coli Proteins; D008962:Models, Theoretical; D008969:Molecular Sequence Data; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000201:enzymology; D017386:Sequence Homology, Amino Acid; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D029968:Escherichia coli Proteins; D065093:beta-Lactamase Inhibitors; C119424:beta-lactamase VEB-1, E coli; D001618:beta-Lactamases
references.citation: Antimicrob Agents Chemother. 2006 Apr;50(4):1525-7
references.pmid: 16569874
references.citation: J Mol Model. 2012 Feb;18(2):755-64
references.pmid: 21594693
references.citation: J Bacteriol. 2001 Jan;183(1):235-49
references.pmid: 11114922
references.citation: J Comput Chem. 2010 Jan 30;31(2):455-61
references.pmid: 19499576
references.citation: J Biol Chem. 2000 Sep 8;275(36):28075-82
references.pmid: 10825176
references.citation: Antimicrob Agents Chemother. 1999 Mar;43(3):573-81
references.pmid: 10049269
references.citation: Antimicrob Agents Chemother. 1993 Apr;37(4):851-8
references.pmid: 8388201
references.citation: Science. 1991 Jul 12;253(5016):164-70
references.pmid: 1853201
references.citation: J Chem Inf Model. 2007 Mar-Apr;47(2):509-14
references.pmid: 17381170
references.citation: Antimicrob Agents Chemother. 2004 Sep;48(9):3284-90
references.pmid: 15328086
references.citation: Antimicrob Agents Chemother. 1994 Jan;38(1):104-14
references.pmid: 8141562
references.citation: Emerg Infect Dis. 2007 May;13(5):803-5
references.pmid: 18044054
references.citation: Emerg Infect Dis. 2001 May-Jun;7(3):468-70
references.pmid: 11384532
references.citation: Philos Trans R Soc Lond B Biol Sci. 1980 May 16;289(1036):309-19
references.pmid: 6109326
references.citation: J Comput Chem. 2004 Oct;25(13):1605-12
references.pmid: 15264254
references.citation: Electrophoresis. 1997 Dec;18(15):2714-23
references.pmid: 9504803
references.citation: J Mol Biol. 1993 Dec 5;234(3):779-815
references.pmid: 8254673
references.citation: Antimicrob Agents Chemother. 1991 Nov;35(11):2294-301
references.pmid: 1804001
references.citation: Nucleic Acids Res. 2000 Jan 1;28(1):235-42
references.pmid: 10592235
references.citation: Clin Microbiol Infect. 2008 Jan;14 Suppl 1:42-52
references.pmid: 18154527
references.citation: Proc Natl Acad Sci U S A. 1990 Sep;87(17):6644-8
references.pmid: 2204060
references.citation: J Antimicrob Chemother. 2006 Jul;58(1):1-6
references.pmid: 16751201
references.citation: Nucleic Acids Res. 2003 Jul 1;31(13):3784-8
references.pmid: 12824418
references.citation: Eur J Clin Microbiol Infect Dis. 2011 Oct;30(10):1267-70
references.pmid: 21442357
references.citation: Nucleic Acids Res. 2003 Jul 1;31(13):3381-5
references.pmid: 12824332
references.citation: Antimicrob Agents Chemother. 1978 Sep;14(3):414-9
references.pmid: 309306
references.citation: J Chem Inf Model. 2005 Jan-Feb;45(1):177-82
references.pmid: 15667143
references.citation: Drug Des Deliv. 1986 Aug;1(1):1-21
references.pmid: 3334541
references.citation: Antimicrob Agents Chemother. 1977 May;11(5):852-7
references.pmid: 879738
references.citation: Bioinformatics. 2006 Jan 15;22(2):195-201
references.pmid: 16301204
references.citation: Phys Rev E Stat Nonlin Soft Matter Phys. 2007 Feb;75(2 Pt 1):021916
references.pmid: 17358376
references.citation: Drug Discov Today. 2008 Jan;13(1-2):23-9
references.pmid: 18190860
references.citation: Antimicrob Agents Chemother. 2006 May;50(5):1745-52
references.pmid: 16641445
references.citation: Proteins. 1990;8(3):195-202
references.pmid: 2281083
references.citation: Nucleic Acids Res. 1997 Sep 1;25(17):3389-402
references.pmid: 9254694
references.citation: J Bacteriol. 2008 Dec;190(24):8053-64
references.pmid: 18931120
references.citation: J Clin Microbiol. 2001 Jan;39(1):175-82
references.pmid: 11136767
references.citation: Clin Microbiol Infect. 2008 Jan;14 Suppl 1:185-8
references.pmid: 18154545
references.citation: Protein Sci. 1993 Sep;2(9):1511-9
references.pmid: 8401235
references.citation: J Antimicrob Chemother. 2008 May;61(5):1029-32
references.pmid: 18292096
references.citation: Proteins. 1999 Jan 1;34(1):4-16
references.pmid: 10336382
references.citation: Cell. 1997 Mar 21;88(6):823-32
references.pmid: 9118225