2. Academic Validation
  3. Exploiting a Cryptic Pocket in DsbA through Structure-Guided Parallel Synthesis and Direct-to-Biology Screening

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

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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