title: Inhibitors of Helicobacter pylori protease HtrA found by 'virtual ligand' screening combat bacterial invasion of epithelia.
abstract: BACKGROUND
  The human pathogen Helicobacter pylori (H. pylori) is a main cause for gastric inflammation and cancer. Increasing bacterial resistance against antibiotics demands for innovative strategies for therapeutic intervention.
  
  
  RESULTS
  We present a method for structure-based virtual screening that is based on the comprehensive prediction of ligand binding sites on a protein model and automated construction of a ligand-receptor interaction map. Pharmacophoric features of the map are clustered and transformed in a correlation vector ('virtual ligand') for rapid virtual screening of compound databases. This computer-based technique was validated for 18 different targets of pharmaceutical interest in a retrospective screening experiment. Prospective screening for inhibitory agents was performed for the protease HtrA from the human pathogen H. pylori using a homology model of the target protein. Among 22 tested compounds six block E-cadherin cleavage by HtrA in vitro and result in reduced scattering and wound healing of gastric epithelial cells, thereby preventing bacterial infiltration of the epithelium.
  
  
  CONCLUSIONS
  This study demonstrates that receptor-based virtual screening with a permissive ('fuzzy') pharmacophore model can help identify small bioactive agents for combating bacterial infection.
authors.affiliation: Institute of Organic Chemistry and Chemical Biology, Goethe-University, Frankfurt, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Löwer
authors.forename: Tim
authors.initials: T
authors.lastname: Geppert
authors.forename: Petra
authors.initials: P
authors.lastname: Schneider
authors.forename: Benjamin
authors.initials: B
authors.lastname: Hoy
authors.forename: Silja
authors.initials: S
authors.lastname: Wessler
authors.forename: Gisbert
authors.initials: G
authors.lastname: Schneider
mesh_terms: D000465:Algorithms; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D045744:Cell Line, Tumor; D016480:Helicobacter pylori / Q000201:enzymology* / Q000502:physiology; D006801:Humans; D008962:Models, Theoretical; D010447:Peptide Hydrolases / Q000737:chemistry* / Q000378:metabolism; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D001426:Bacterial Proteins; D011480:Protease Inhibitors; D010447:Peptide Hydrolases