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Identification and Validation Novel of VIM‐2 Metallo‐β‐lactamase Tripeptide Inhibitors
Author(s) -
Xiao Jing,
Fang Mi,
Shi Yun,
Chen Hui,
Shen Bingzhen,
Chen Jiao,
Lao Xingzhen,
Xu Hanmei,
Zheng Heng
Publication year - 2015
Publication title -
molecular informatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.481
H-Index - 68
eISSN - 1868-1751
pISSN - 1868-1743
DOI - 10.1002/minf.201400178
Subject(s) - tripeptide , pharmacophore , virtual screening , docking (animal) , chemistry , peptide , in vitro , enzyme , computational biology , combinatorial chemistry , biochemistry , stereochemistry , biology , medicine , nursing
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 IC 50 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.