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

Luke F Duncan; Geqing Wang; Olga V Ilyichova; Rabeb Dhouib; Makrina Totsika; Martin J Scanlon; Begoña Heras; Belinda M Abbott

doi:10.1016/j.bmc.2021.116315

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. 2021 Sep 1:45:116315. doi: 10.1016/j.bmc.2021.116315. Epub 2021 Jul 22.

Authors

Luke F Duncan¹, Geqing Wang², Olga V Ilyichova³, Rabeb Dhouib⁴, Makrina Totsika⁴, Martin J Scanlon⁵, Begoña Heras⁶, Belinda M Abbott⁷

Affiliations

¹ Department of Chemistry and Physics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia.
² Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia.
³ Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia.
⁴ Centre for Immunology and Infection Control, School of Biomedical Sciences, Queensland University of Technology, Brisbane, Queensland, Australia.
⁵ Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia; ARC Training Centre for Fragment Based Design, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia.
⁶ Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia. Electronic address: [email protected].
⁷ Department of Chemistry and Physics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia. Electronic address: [email protected].

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

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.

Keywords: Antivirulence; Benzofuran; DsbA; Enzyme inhibition; Fragment-based drug discovery; Oxidoreductase.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Benzofurans / chemical synthesis
Benzofurans / chemistry
Benzofurans / pharmacology*
Crystallography, X-Ray
Dose-Response Relationship, Drug
Drug Design*
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Escherichia coli Proteins / antagonists & inhibitors*
Escherichia coli Proteins / metabolism
Models, Molecular
Molecular Structure
Protein Disulfide-Isomerases / antagonists & inhibitors*
Protein Disulfide-Isomerases / metabolism
Structure-Activity Relationship

Substances

Benzofurans
Enzyme Inhibitors
Escherichia coli Proteins
Protein Disulfide-Isomerases
dsbA protein, E coli
benzofuran