7LHP

Crystal Structure of EcDsbA in a complex with methyl 2-(6-bromo-2-phenylbenzofuran-3-yl)acetate

Summary for 7LHP

• Entry DOI: 10.2210/pdb7lhp/pdb
• Descriptor: Thiol:disulfide interchange protein DsbA, (6-bromo-2-phenyl-1-benzofuran-3-yl)acetic acid, COPPER (II) ION, ... (4 entities in total)
• Functional Keywords: disulfide oxidoreductase, redox protein, oxidoreductase-inhibitor complex, oxidoreductase, oxidoreductase/inhibitor
• Biological source: Escherichia coli (strain K12)
• Total number of polymer chains: 2
• Total formula weight: 42704.76

Authors

Ilyichova, O.V.,Scanlon, M.J. (deposition date: 2021-01-26, release date: 2021-08-11, Last modification date: 2024-11-13)

Primary citation

Duncan, L.F.,Wang, G.,Ilyichova, O.V.,Dhouib, R.,Totsika, M.,Scanlon, M.J.,Heras, B.,Abbott, B.M.
Elaboration of a benzofuran scaffold and evaluation of binding affinity and inhibition of Escherichia coli DsbA: A fragment-based drug design approach to novel antivirulence compounds.
Bioorg.Med.Chem., 45:116315-116315, 2021

PubMed Abstract: Bacterial thiol-disulfide oxidoreductase DsbA is essential for bacterial virulence factor assembly and has been identified as a viable antivirulence target. Herein, we report a structure-based elaboration of a benzofuran hit that bound to the active site groove of Escherichia coli DsbA. Substituted phenyl groups were installed at the 5- and 6-position of the benzofuran using Suzuki-Miyaura coupling. HSQC NMR titration experiments showed dissociation constants of this series in the high µM to low mM range and X-ray crystallography produced three co-structures, showing binding in the hydrophobic groove, comparable with that of the previously reported benzofurans. The 6-(m-methoxy)phenyl analogue (2b), which showed a promising binding pose, was chosen for elaboration from the C-2 position. The 2,6-disubstituted analogues bound to the hydrophobic region of the binding groove and the C-2 groups extended into the more polar, previously un-probed, region of the binding groove. Biochemical analysis of the 2,6-disubsituted analogues showed they inhibited DsbA oxidation activity in vitro. The results indicate the potential to develop the elaborated benzofuran series into a novel class of antivirulence compounds.

PubMed: 34364222
DOI: 10.1016/j.bmc.2021.116315

Experimental method

X-RAY DIFFRACTION (1.9 Å)