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Open AccessArticle

The Fragment-Based Development of a Benzofuran Hit as a New Class of Escherichia coli DsbA Inhibitors

1
Department of Chemistry and Physics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne 3086, Australia
2
Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne 3086, Australia
3
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville 3052, Australia
4
ARC Training Centre for Fragment Based Design, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville 3052, Australia
*
Author to whom correspondence should be addressed.
These authors contributed equally to this paper.
Academic Editor: Brian J. Stockman
Molecules 2019, 24(20), 3756; https://doi.org/10.3390/molecules24203756
Received: 9 September 2019 / Revised: 13 October 2019 / Accepted: 15 October 2019 / Published: 18 October 2019
(This article belongs to the Special Issue Fragment Based Drug Discovery)
A fragment-based drug discovery approach was taken to target the thiol-disulfide oxidoreductase enzyme DsbA from Escherichia coli (EcDsbA). This enzyme is critical for the correct folding of virulence factors in many pathogenic Gram-negative bacteria, and small molecule inhibitors can potentially be developed as anti-virulence compounds. Biophysical screening of a library of fragments identified several classes of fragments with affinity to EcDsbA. One hit with high mM affinity, 2-(6-bromobenzofuran-3-yl)acetic acid (6), was chemically elaborated at several positions around the scaffold. X-ray crystal structures of the elaborated analogues showed binding in the hydrophobic binding groove adjacent to the catalytic disulfide bond of EcDsbA. Binding affinity was calculated based on NMR studies and compounds 25 and 28 were identified as the highest affinity binders with dissociation constants (KD) of 326 ± 25 and 341 ± 57 µM respectively. This work suggests the potential to develop benzofuran fragments into a novel class of EcDsbA inhibitors. View Full-Text
Keywords: fragment-based drug discovery; Escherichia coli; antibiotic resistance; DsbA inhibition; benzofuran; disulfide bond; bacterial virulence fragment-based drug discovery; Escherichia coli; antibiotic resistance; DsbA inhibition; benzofuran; disulfide bond; bacterial virulence
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MDPI and ACS Style

Duncan, L.F.; Wang, G.; Ilyichova, O.V.; Scanlon, M.J.; Heras, B.; Abbott, B.M. The Fragment-Based Development of a Benzofuran Hit as a New Class of Escherichia coli DsbA Inhibitors. Molecules 2019, 24, 3756.

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