Fragment-Based De Novo Design Reveals a Small-Molecule Inhibitor of Helicobacter Pylori HtrA

Angew Chem Int Ed Engl. 2015 Aug 24;54(35):10244-8. doi: 10.1002/anie.201504035. Epub 2015 Jun 9.

Abstract

Sustained identification of innovative chemical entities is key for the success of chemical biology and drug discovery. We report the fragment-based, computer-assisted de novo design of a small molecule inhibiting Helicobacter pylori HtrA protease. Molecular binding of the designed compound to HtrA was confirmed through biophysical methods, supporting its functional activity in vitro. Hit expansion led to the identification of the currently best-in-class HtrA inhibitor. The results obtained reinforce the validity of ligand-based de novo design and binding-kinetics-guided optimization for the efficient discovery of pioneering lead structures and prototyping drug-like chemical probes with tailored bioactivity.

Keywords: biophysical methods; chemical biology; computer-assisted drug design; drug design; receptor-ligand interactions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bacterial Proteins / antagonists & inhibitors*
  • Computer-Aided Design
  • Drug Design*
  • Drug Discovery
  • Helicobacter Infections / drug therapy*
  • Helicobacter Infections / microbiology
  • Helicobacter pylori / drug effects*
  • Helicobacter pylori / enzymology
  • Humans
  • Ligands
  • Peptide Hydrolases / chemistry*
  • Protease Inhibitors / pharmacology*
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship

Substances

  • Bacterial Proteins
  • Ligands
  • Protease Inhibitors
  • Small Molecule Libraries
  • Peptide Hydrolases