Exploiting a Cryptic Pocket in DsbA through Structure-Guided Parallel Synthesis and Direct-to-Biology Screening

  • J Med Chem. 2026 Mar 26;69(6):6760-6774. doi: 10.1021/acs.jmedchem.5c03004.
Yildiz Tasdan  1  2 ,  Gautham R Balaji  1  3 ,  James Davidson  4 ,  Naureen Akhtar  1  3 ,  Olga Ilyichova  1 ,  Lucie J Guetzoyan  4 ,  Indu R Chandrashekaran  1  3 ,  Wesam Alwan  1 ,  Helen Cobb  4 ,  Menachem J Gunzburg  1  3 ,  AbdulBasir Hasanzada  4 ,  Stephen D Roughley  4 ,  James B Murray  4 ,  Van C Thai  5 ,  Tessa Cliff  5 ,  Charlene M Kahler  5 ,  Biswaranjan Mohanty  1  2 ,  Ben Capuano  1  2 ,  Bradley C Doak  1  3 ,  Martin J Scanlon  1  2  3
Affiliations
  • 1. Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia.
  • 2. ARC Centre for Fragment-Based Design, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia.
  • 3. Monash Fragment Platform, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia.
  • 4. Vernalis (R&D) Ltd, Granta Park, Great Abington, CB21 6GB Cambridge, U.K.
  • 5. Marshall Centre for Infectious Diseases, Research and Training, School of Biomedical Sciences, University of Western Australia, 35 Stirling Highway, Perth 6009, Australia.
PMID: 41789772 DOI: 10.1021/acs.jmedchem.5c03004
Abstract

Antibacterial resistance is a major global health problem, causing an increasing number of deaths worldwide. DsbA, a Bacterial oxidoreductase enzyme, is pivotal for the correct folding and activity of virulence factors in bacteria. Inhibiting DsbA presents a promising avenue for developing antivirulence compounds and combating Bacterial resistance. The enzyme's structure features two ligand-binding sites: a hydrophobic groove that is the binding site for natural peptide substrates and a "cryptic pocket" enclosed within the protein, which has recently been identified as a target for ligand design. In this study, we report the elaboration of a fragment from within the enclosed cryptic pocket into the hydrophobic groove of Escherichia coli DsbA, using X-ray crystallography-guided structure-based design and parallel synthesis coupled with crude reaction mixture screening (direct-to-biology). This effort yielded the most potent small-molecule EcDsbA inhibitors reported to date and exemplifies a productive strategy for exploiting a cryptic pocket for drug development.

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