Abstract
The β-clamp is the processivity-promoting factor for most of the enzymes in prokaryotic DNA replication; hence, it is a crucial drug target. In the present study, we investigated the β-clamp from Helicobacter pylori, aiming to seek potential drug molecules against this gastric-cancer-causing bacterium. An in silico screening of Food and Drug Administration (FDA) approved drugs against the H. pylori β-clamp, followed by its in vitro inhibition using a surface competition approach, yielded the drug diflunisal as a positive initial hit. Diflunisal inhibits the growth of H. pylori in the micromolar range. We determined the structure of diflunisal in complex with the β-clamp to show that the drug binds at subsite I, which is a protein-protein interaction site. Successful identification of FDA-approved molecules against H. pylori may lead to better and faster drug development.
Original language | English |
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Pages (from-to) | 2311-2322 |
Number of pages | 12 |
Journal | FEBS Letters |
Volume | 591 |
Issue number | 15 |
DOIs | |
Publication status | Published - Aug 2017 |
Keywords
- Anti-Bacterial Agents/chemistry
- Binding Sites
- Crystallography, X-Ray
- DNA Ligases/metabolism
- DNA Polymerase III/antagonists & inhibitors
- Diflunisal/chemistry
- Drug Approval
- Drug Evaluation, Preclinical/methods
- Enzyme Inhibitors/chemistry
- Helicobacter pylori/drug effects
- Inhibitory Concentration 50
- Molecular Docking Simulation
- Protein Conformation
- United States
- United States Food and Drug Administration