Targeting the β-clamp in Helicobacter pylori with FDA-approved drugs reveals micromolar inhibition by diflunisal

Preeti Pandey, Vijay Verma, Gunjan Gautam, Nilima Kumari, Suman Kumar Dhar, Samudrala Gourinath

Research output: Contribution to journalArticle (Academic Journal)peer-review

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 languageEnglish
Pages (from-to)2311-2322
Number of pages12
JournalFEBS Letters
Volume591
Issue number15
DOIs
Publication statusPublished - 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

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