6PVZ

E.coli DsbA in complex with benzofuran compound 28 ((6-benzyl-1-benzofuran-3-yl)acetic acid)

Summary for 6PVZ

• Entry DOI: 10.2210/pdb6pvz/pdb
• Descriptor: Thiol:disulfide interchange protein DsbA, (6-benzyl-1-benzofuran-3-yl)acetic acid, COPPER (II) ION, ... (4 entities in total)
• Functional Keywords: inhibitor, complex, disulfide oxidoreductase, fragments, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Escherichia coli (strain K12)
• Total number of polymer chains: 2
• Total formula weight: 42639.89

Authors

Wang, G.,Heras, B. (deposition date: 2019-07-21, release date: 2019-12-25, Last modification date: 2024-10-23)

Primary citation

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, 24:-, 2019

PubMed Abstract: A fragment-based drug discovery approach was taken to target the thiol-disulfide oxidoreductase enzyme DsbA from (DsbA). 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 DsbA. One hit with high mM affinity, 2-(6-bromobenzofuran-3-yl)acetic acid (), 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 DsbA. Binding affinity was calculated based on NMR studies and compounds and were identified as the highest affinity binders with dissociation constants () of 326 ± 25 and 341 ± 57 µM respectively. This work suggests the potential to develop benzofuran fragments into a novel class of DsbA inhibitors.

PubMed: 31635355
DOI: 10.3390/molecules24203756

Experimental method

X-RAY DIFFRACTION (1.99 Å)