title: Homology modeling and virtual screening of inhibitors against TEM- and SHV-type-resistant mutants: A multilayer filtering approach.
abstract: 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.
authors.affiliation: Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, India.|School of Biotechnology, Yeungnam University, Gyeongsan, Republic of Korea.
authors.forename: Mohammad H
authors.initials: MH
authors.lastname: Baig
authors.affiliation: Division of Medicinal Chemistry and Drug Discovery, Global Institute of Pharmaceutical Education and Research, Kashipur, Udham Singh Nagar, Uttarakhand, India.
authors.forename: Vishal M
authors.initials: VM
authors.lastname: Balaramnavar
authors.affiliation: Department of Biotechnology, Government of India, New Delhi, India.
authors.forename: Gulshan
authors.initials: G
authors.lastname: Wadhwa
authors.affiliation: Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, India.
authors.forename: Asad U
authors.initials: AU
authors.lastname: Khan
mesh_terms: D000595:Amino Acid Sequence; D020134:Catalytic Domain; D004353:Drug Evaluation, Preclinical; D024881:Drug Resistance, Bacterial / Q000187:drug effects* / Q000235:genetics; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D009154:Mutation; D017386:Sequence Homology, Amino Acid; D014584:User-Computer Interface; D014867:Water / Q000737:chemistry; D065093:beta-Lactamase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D001618:beta-Lactamases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D065093:beta-Lactamase Inhibitors; D014867:Water; D001618:beta-Lactamases
keywords: Molecular docking; Pharmacophore; SHV; TEM; Virtual Screening; inhibitor resistance; β-lactamases