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Issue 2, 2017
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NMR-filtered virtual screening leads to non-metal chelating metallo-β-lactamase inhibitors

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Abstract

There are no clinically useful inhibitors of metallo-β-lactamases (MBLs), which are a growing problem because they hydrolyse almost all β-lactam antibacterials. Inhibition by most reported MBL inhibitors involves zinc ion chelation. A structure-based virtual screening approach combined with NMR filtering led to the identification of inhibitors of the clinically relevant Verona Integron-encoded MBL (VIM)-2. Crystallographic analyses reveal a new mode of MBL inhibition involving binding adjacent to the active site zinc ions, but which does not involve metal chelation. The results will aid efforts to develop new types of clinically useful inhibitors targeting MBLs/MBL-fold metallo-enzymes involved in antibacterial and anticancer drug resistance.

Graphical abstract: NMR-filtered virtual screening leads to non-metal chelating metallo-β-lactamase inhibitors

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Supplementary files

Article information


Submitted
10 Oct 2016
Accepted
13 Dec 2016
First published
14 Dec 2016

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2017,8, 928-937
Article type
Edge Article

NMR-filtered virtual screening leads to non-metal chelating metallo-β-lactamase inhibitors

G. Li, M. I. Abboud, J. Brem, H. Someya, C. T. Lohans, S. Yang, J. Spencer, D. W. Wareham, M. A. McDonough and C. J. Schofield, Chem. Sci., 2017, 8, 928
DOI: 10.1039/C6SC04524C

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