Cargando…

Discovery of Novel New Delhi Metallo-β-Lactamases-1 Inhibitors by Multistep Virtual Screening

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 sele...

Descripción completa

Detalles Bibliográficos
Autores principales: Wang, Xuequan, Lu, Meiling, Shi, Yang, Ou, Yu, Cheng, Xiaodong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4348537/
https://www.ncbi.nlm.nih.gov/pubmed/25734558
http://dx.doi.org/10.1371/journal.pone.0118290
_version_ 1782359939229941760
author Wang, Xuequan
Lu, Meiling
Shi, Yang
Ou, Yu
Cheng, Xiaodong
author_facet Wang, Xuequan
Lu, Meiling
Shi, Yang
Ou, Yu
Cheng, Xiaodong
author_sort Wang, Xuequan
collection PubMed
description 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 IC(50) values were validated. The most potent inhibitor, VNI-41, inhibited NDM-1 with an IC(50) 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.
format Online
Article
Text
id pubmed-4348537
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-43485372015-03-06 Discovery of Novel New Delhi Metallo-β-Lactamases-1 Inhibitors by Multistep Virtual Screening Wang, Xuequan Lu, Meiling Shi, Yang Ou, Yu Cheng, Xiaodong PLoS One Research Article 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 IC(50) values were validated. The most potent inhibitor, VNI-41, inhibited NDM-1 with an IC(50) 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. Public Library of Science 2015-03-03 /pmc/articles/PMC4348537/ /pubmed/25734558 http://dx.doi.org/10.1371/journal.pone.0118290 Text en © 2015 Wang et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Wang, Xuequan
Lu, Meiling
Shi, Yang
Ou, Yu
Cheng, Xiaodong
Discovery of Novel New Delhi Metallo-β-Lactamases-1 Inhibitors by Multistep Virtual Screening
title Discovery of Novel New Delhi Metallo-β-Lactamases-1 Inhibitors by Multistep Virtual Screening
title_full Discovery of Novel New Delhi Metallo-β-Lactamases-1 Inhibitors by Multistep Virtual Screening
title_fullStr Discovery of Novel New Delhi Metallo-β-Lactamases-1 Inhibitors by Multistep Virtual Screening
title_full_unstemmed Discovery of Novel New Delhi Metallo-β-Lactamases-1 Inhibitors by Multistep Virtual Screening
title_short Discovery of Novel New Delhi Metallo-β-Lactamases-1 Inhibitors by Multistep Virtual Screening
title_sort discovery of novel new delhi metallo-β-lactamases-1 inhibitors by multistep virtual screening
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4348537/
https://www.ncbi.nlm.nih.gov/pubmed/25734558
http://dx.doi.org/10.1371/journal.pone.0118290
work_keys_str_mv AT wangxuequan discoveryofnovelnewdelhimetalloblactamases1inhibitorsbymultistepvirtualscreening
AT lumeiling discoveryofnovelnewdelhimetalloblactamases1inhibitorsbymultistepvirtualscreening
AT shiyang discoveryofnovelnewdelhimetalloblactamases1inhibitorsbymultistepvirtualscreening
AT ouyu discoveryofnovelnewdelhimetalloblactamases1inhibitorsbymultistepvirtualscreening
AT chengxiaodong discoveryofnovelnewdelhimetalloblactamases1inhibitorsbymultistepvirtualscreening