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In Silico Fragment-Based Design Identifies Subfamily B1 Metallo-β-lactamase Inhibitors

Research output: Contribution to journalArticle

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In Silico Fragment-Based Design Identifies Subfamily B1 Metallo-β-lactamase Inhibitors. / Cain, Ricky; Brem, Jürgen; Zollman, David; McDonough, Michael A.; Johnson, Rachel M.; Spencer, James; Makena, Anne; Abboud, Martine I.; Cahill, Samuel; Lee, Sook Y.; McHugh, Peter J.; Schofield, Christopher J.; Fishwick, Colin W.G.

In: Journal of Medicinal Chemistry, Vol. 61, No. 3, 08.02.2018, p. 1255-1260.

Research output: Contribution to journalArticle

Harvard

Cain, R, Brem, J, Zollman, D, McDonough, MA, Johnson, RM, Spencer, J, Makena, A, Abboud, MI, Cahill, S, Lee, SY, McHugh, PJ, Schofield, CJ & Fishwick, CWG 2018, 'In Silico Fragment-Based Design Identifies Subfamily B1 Metallo-β-lactamase Inhibitors', Journal of Medicinal Chemistry, vol. 61, no. 3, pp. 1255-1260. https://doi.org/10.1021/acs.jmedchem.7b01728

APA

Cain, R., Brem, J., Zollman, D., McDonough, M. A., Johnson, R. M., Spencer, J., ... Fishwick, C. W. G. (2018). In Silico Fragment-Based Design Identifies Subfamily B1 Metallo-β-lactamase Inhibitors. Journal of Medicinal Chemistry, 61(3), 1255-1260. https://doi.org/10.1021/acs.jmedchem.7b01728

Vancouver

Cain R, Brem J, Zollman D, McDonough MA, Johnson RM, Spencer J et al. In Silico Fragment-Based Design Identifies Subfamily B1 Metallo-β-lactamase Inhibitors. Journal of Medicinal Chemistry. 2018 Feb 8;61(3):1255-1260. https://doi.org/10.1021/acs.jmedchem.7b01728

Author

Cain, Ricky ; Brem, Jürgen ; Zollman, David ; McDonough, Michael A. ; Johnson, Rachel M. ; Spencer, James ; Makena, Anne ; Abboud, Martine I. ; Cahill, Samuel ; Lee, Sook Y. ; McHugh, Peter J. ; Schofield, Christopher J. ; Fishwick, Colin W.G. / In Silico Fragment-Based Design Identifies Subfamily B1 Metallo-β-lactamase Inhibitors. In: Journal of Medicinal Chemistry. 2018 ; Vol. 61, No. 3. pp. 1255-1260.

Bibtex

@article{774d166373c7491b873c1de976ecdd10,
title = "In Silico Fragment-Based Design Identifies Subfamily B1 Metallo-β-lactamase Inhibitors",
abstract = "Zinc ion-dependent β-lactamases (MBLs) catalyze the hydrolysis of almost all β-lactam antibiotics and resist the action of clinically available β-lactamase inhibitors. We report how application of in silico fragment-based molecular design employing thiol-mediated metal anchorage leads to potent MBL inhibitors. The new inhibitors manifest potent inhibition of clinically important B1 subfamily MBLs, including the widespread NDM-1, IMP-1, and VIM-2 enzymes; with lower potency, some of them also inhibit clinically relevant Class A and D serine-β-lactamases. The inhibitors show selectivity for bacterial MBL enzymes compared to that for human MBL fold nucleases. Cocrystallization of one inhibitor, which shows potentiation of Meropenem activity against MBL-expressing Enterobacteriaceae, with VIM-2 reveals an unexpected binding mode, involving interactions with residues from conserved active site bordering loops.",
author = "Ricky Cain and J{\"u}rgen Brem and David Zollman and McDonough, {Michael A.} and Johnson, {Rachel M.} and James Spencer and Anne Makena and Abboud, {Martine I.} and Samuel Cahill and Lee, {Sook Y.} and McHugh, {Peter J.} and Schofield, {Christopher J.} and Fishwick, {Colin W.G.}",
year = "2018",
month = "2",
day = "8",
doi = "10.1021/acs.jmedchem.7b01728",
language = "English",
volume = "61",
pages = "1255--1260",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "3",

}

RIS - suitable for import to EndNote

TY - JOUR

T1 - In Silico Fragment-Based Design Identifies Subfamily B1 Metallo-β-lactamase Inhibitors

AU - Cain, Ricky

AU - Brem, Jürgen

AU - Zollman, David

AU - McDonough, Michael A.

AU - Johnson, Rachel M.

AU - Spencer, James

AU - Makena, Anne

AU - Abboud, Martine I.

AU - Cahill, Samuel

AU - Lee, Sook Y.

AU - McHugh, Peter J.

AU - Schofield, Christopher J.

AU - Fishwick, Colin W.G.

PY - 2018/2/8

Y1 - 2018/2/8

N2 - Zinc ion-dependent β-lactamases (MBLs) catalyze the hydrolysis of almost all β-lactam antibiotics and resist the action of clinically available β-lactamase inhibitors. We report how application of in silico fragment-based molecular design employing thiol-mediated metal anchorage leads to potent MBL inhibitors. The new inhibitors manifest potent inhibition of clinically important B1 subfamily MBLs, including the widespread NDM-1, IMP-1, and VIM-2 enzymes; with lower potency, some of them also inhibit clinically relevant Class A and D serine-β-lactamases. The inhibitors show selectivity for bacterial MBL enzymes compared to that for human MBL fold nucleases. Cocrystallization of one inhibitor, which shows potentiation of Meropenem activity against MBL-expressing Enterobacteriaceae, with VIM-2 reveals an unexpected binding mode, involving interactions with residues from conserved active site bordering loops.

AB - Zinc ion-dependent β-lactamases (MBLs) catalyze the hydrolysis of almost all β-lactam antibiotics and resist the action of clinically available β-lactamase inhibitors. We report how application of in silico fragment-based molecular design employing thiol-mediated metal anchorage leads to potent MBL inhibitors. The new inhibitors manifest potent inhibition of clinically important B1 subfamily MBLs, including the widespread NDM-1, IMP-1, and VIM-2 enzymes; with lower potency, some of them also inhibit clinically relevant Class A and D serine-β-lactamases. The inhibitors show selectivity for bacterial MBL enzymes compared to that for human MBL fold nucleases. Cocrystallization of one inhibitor, which shows potentiation of Meropenem activity against MBL-expressing Enterobacteriaceae, with VIM-2 reveals an unexpected binding mode, involving interactions with residues from conserved active site bordering loops.

UR - http://www.scopus.com/inward/record.url?scp=85042121524&partnerID=8YFLogxK

U2 - 10.1021/acs.jmedchem.7b01728

DO - 10.1021/acs.jmedchem.7b01728

M3 - Article

C2 - 29271657

AN - SCOPUS:85042121524

VL - 61

SP - 1255

EP - 1260

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 3

ER -