Homology modeling and virtual screening of inhibitors against TEM- and SHV-type-resistant mutants: A multilayer filtering approach.

Publisher: Wiley-Blackwell Country of Publication: United States NLM ID: 8609465 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1470-8744 (Electronic) Linking ISSN: 08854513 NLM ISO Abbreviation: Biotechnol Appl Biochem Subsets: MEDLINE

Publication: Jan. 2011- : Malden : Wiley-Blackwell
Original Publication: San Diego : Academic Press, [cl986]-

Models, Molecular* ; Mutation* ; Sequence Homology, Amino Acid*; Drug Resistance, Bacterial/*drug effects ; beta-Lactamase Inhibitors/*pharmacology ; beta-Lactamases/*chemistry ; beta-Lactamases/*metabolism; Amino Acid Sequence ; Catalytic Domain ; Drug Evaluation, Preclinical ; Drug Resistance, Bacterial/genetics ; Molecular Docking Simulation ; Molecular Sequence Data ; User-Computer Interface ; Water/chemistry ; beta-Lactamase Inhibitors/metabolism ; beta-Lactamases/genetics

TEM and SHV are class-A-type β-lactamases commonly found in Escherichia coli and Klebsiella pneumoniae. Previous studies reported S130G and K234R mutations in SHVs to be 41- and 10-fold more resistant toward clavulanic acid than SHV-1, respectively, whereas TEM S130G and R244S also showed the same level of resistance. These selected mutants confer higher level of resistance against clavulanic acid. They also show little susceptibility against other commercially available β-lactamase inhibitors. In this study, we have used docking-based virtual screening approach in order to screen potential inhibitors against some of the major resistant mutants of SHV and TEM types β-lactamase. Two different inhibitor-resistant mutants from SHV and TEM were selected. Moreover, we have retained the active site water molecules within each enzyme. Active site water molecules were placed within modeled structure of the mutant whose structure was unavailable with protein databank. The novelty of this work lies in the use of multilayer virtual screening approach for the prediction of best and accurate results. We are reporting five inhibitors on the basis of their efficacy against all the selected resistant mutants. These inhibitors were selected on the basis of their binding efficacies and pharmacophore features.
(© 2015 International Union of Biochemistry and Molecular Biology, Inc.)

Keywords: Molecular docking; Pharmacophore; SHV; TEM; Virtual Screening; inhibitor resistance; β-lactamases

0 (beta-Lactamase Inhibitors)
059QF0KO0R (Water)
EC 3.5.2.6 (beta-Lactamases)

Date Created: 20150318 Date Completed: 20160727 Latest Revision: 20151020

20250114

10.1002/bab.1370

25779642