Discovery of novel new Delhi metallo-β-lactamases-1 inhibitors by multistep virtual screening

PloS One
Xuequan WangXiaodong Cheng

Abstract

The emergence of NDM-1 containing multi-antibiotic resistant "Superbugs" necessitates the needs of developing of novel NDM-1inhibitors. In this study, we report the discovery of novel NDM-1 inhibitors by multi-step virtual screening. From a 2,800,000 virtual drug-like compound library selected from the ZINC database, we generated a focused NDM-1 inhibitor library containing 298 compounds of which 44 chemical compounds were purchased and evaluated experimentally for their ability to inhibit NDM-1 in vitro. Three novel NDM-1 inhibitors with micromolar IC50 values were validated. The most potent inhibitor, VNI-41, inhibited NDM-1 with an IC50 of 29.6 ± 1.3 μM. Molecular dynamic simulation revealed that VNI-41 interacted extensively with the active site. In particular, the sulfonamide group of VNI-41 interacts directly with the metal ion Zn1 that is critical for the catalysis. These results demonstrate the feasibility of applying virtual screening methodologies in identifying novel inhibitors for NDM-1, a metallo-β-lactamase with a malleable active site and provide a mechanism base for rational design of NDM-1 inhibitors using sulfonamide as a functional scaffold.

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Citations

Feb 1, 2019·Clinical Microbiology Reviews·Wenjing WuZhiyong Zong
Jun 3, 2016·Future Medicinal Chemistry·Paul W GroundwaterDavid E Hibbs
Mar 30, 2019·Chemical Biology & Drug Design·Cheng ShiHeng Zheng
Aug 15, 2018·Journal of Chemical Information and Modeling·Joon S KangPeter Oelschlaeger
Nov 14, 2018·ACS Infectious Diseases·Pasquale LincianoDonatella Tondi

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Methods Mentioned

BETA
X-ray

Software Mentioned

Molecular Operating Environment suit ( MOE
MOE
LigX
Protein Model Portal ( PMP )
Discovery Studio ( ADS
Origin
ADS
libdock
GridMIn

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