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Targeting the β‐clamp in Helicobacter pylori with <scp>FDA</scp> ‐approved drugs reveals micromolar inhibition by diflunisal
- Source :
- FEBS Letters. 591:2311-2322
- Publication Year :
- 2017
- Publisher :
- Wiley, 2017.
-
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.
- Subjects :
- 0301 basic medicine
Drug
DNA Ligases
Protein Conformation
media_common.quotation_subject
Drug Evaluation, Preclinical
Biophysics
Diflunisal
Pharmacology
Crystallography, X-Ray
Biochemistry
Inhibitory Concentration 50
03 medical and health sciences
0302 clinical medicine
Non-competitive inhibition
Structural Biology
Genetics
medicine
Enzyme Inhibitors
Binding site
Drug Approval
Molecular Biology
DNA Polymerase III
media_common
chemistry.chemical_classification
Binding Sites
Helicobacter pylori
biology
United States Food and Drug Administration
Chemistry
Cell Biology
biology.organism_classification
United States
Anti-Bacterial Agents
Molecular Docking Simulation
030104 developmental biology
Enzyme
Drug development
Prokaryotic DNA replication
030220 oncology & carcinogenesis
medicine.drug
Subjects
Details
- ISSN :
- 18733468 and 00145793
- Volume :
- 591
- Database :
- OpenAIRE
- Journal :
- FEBS Letters
- Accession number :
- edsair.doi.dedup.....44c7b78c2b4f1aa2e5a3b8cfd0ee1f68