title: Identification and Validation Novel of VIM-2 Metallo-β-lactamase Tripeptide Inhibitors.
abstract: The development of novel inhibitors against metallo-β-lactamase is essential to remedy metallo-β-lactamase mediated bacterial resistance. A recently emerged metallo-β-lactamase, VIM-2, has demonstrated resistance to existing β-lactamase inhibitors in the clinic. In this study, a hybrid virtual screening protocol that combines pharmacophore modeling, molecular docking, and calculation of binding free energy was employed to screen an internal tripeptide database for novel inhibitors against VIM-2. This resulted in four tripeptides (WWC, WCW, MCW, YCW) as potential inhibitors, and their effects on VIM-2 metallo-β-lactamase were subsequently tested in vitro. Significantly, two peptides (MCW, YCW) exhibited potent inhibitory activities with IC50 values of 18.15 µM and 52.9 µM, respectively. To our knowledge, this is the first study that employed the hybrid virtual screening of combinational peptide database and discovered potent peptide inhibitors of VIM-2 metallo-β-lactamase.
authors.affiliation: Pharmaceutical Bioinformatics, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China, Tel.:+86 25 83271001. Fax: +86 25 8327249.
authors.forename: Jing
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Pharmaceutical Bioinformatics, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China, Tel.:+86 25 83271001. Fax: +86 25 8327249.
authors.forename: Mi
authors.initials: M
authors.lastname: Fang
authors.affiliation: Pharmaceutical Bioinformatics, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China, Tel.:+86 25 83271001. Fax: +86 25 8327249.
authors.forename: Yun
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Pharmaceutical Bioinformatics, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China, Tel.:+86 25 83271001. Fax: +86 25 8327249.
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.affiliation: Pharmaceutical Bioinformatics, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China, Tel.:+86 25 83271001. Fax: +86 25 8327249.
authors.forename: Bingzhen
authors.initials: B
authors.lastname: Shen
authors.affiliation: Pharmaceutical Bioinformatics, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China, Tel.:+86 25 83271001. Fax: +86 25 8327249.
authors.forename: Jiao
authors.initials: J
authors.lastname: Chen
authors.affiliation: Pharmaceutical Bioinformatics, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China, Tel.:+86 25 83271001. Fax: +86 25 8327249.
authors.forename: Xingzhen
authors.initials: X
authors.lastname: Lao
authors.affiliation: Pharmaceutical Bioinformatics, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China, Tel.:+86 25 83271001. Fax: +86 25 8327249. xuhanmei@cpu.edu.cn.
authors.forename: Hanmei
authors.initials: H
authors.lastname: Xu
authors.affiliation: Pharmaceutical Bioinformatics, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China, Tel.:+86 25 83271001. Fax: +86 25 8327249. zhengh18@hotmail.com.
authors.forename: Heng
authors.initials: H
authors.lastname: Zheng
mesh_terms: D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D062105:Molecular Docking Simulation; D009842:Oligopeptides / Q000737:chemistry*; D065093:beta-Lactamase Inhibitors / Q000737:chemistry*; D001618:beta-Lactamases / Q000737:chemistry*
chemical_list: D001426:Bacterial Proteins; D009842:Oligopeptides; D065093:beta-Lactamase Inhibitors; C425108:beta-lactamase bla(vim-2); D001618:beta-Lactamases
keywords: Bacterial resistance; Docking; Pharmacophore hypothesis; Tripeptide inhibitors; VIM-2 metallo-β-lactamase