Document Detail

Inhibitors of Helicobacter pylori protease HtrA found by 'virtual ligand' screening combat bacterial invasion of epithelia.
MedLine Citation:
PMID:  21483848     Owner:  NLM     Status:  MEDLINE    
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.
METHODOLOGY/PRINCIPAL FINDINGS: 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/SIGNIFICANCE: This study demonstrates that receptor-based virtual screening with a permissive ('fuzzy') pharmacophore model can help identify small bioactive agents for combating bacterial infection.
Martin Löwer; Tim Geppert; Petra Schneider; Benjamin Hoy; Silja Wessler; Gisbert Schneider
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Publication Detail:
Type:  Journal Article     Date:  2011-03-31
Journal Detail:
Title:  PloS one     Volume:  6     ISSN:  1932-6203     ISO Abbreviation:  PLoS ONE     Publication Date:  2011  
Date Detail:
Created Date:  2011-04-12     Completed Date:  2011-08-25     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  101285081     Medline TA:  PLoS One     Country:  United States    
Other Details:
Languages:  eng     Pagination:  e17986     Citation Subset:  IM    
Institute of Organic Chemistry and Chemical Biology, Goethe-University, Frankfurt, Germany.
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MeSH Terms
Bacterial Proteins / antagonists & inhibitors*,  chemistry
Cell Line, Tumor
Helicobacter pylori / enzymology*,  physiology
Models, Theoretical*
Peptide Hydrolases / chemistry*,  metabolism
Protease Inhibitors / chemistry*,  pharmacology
Structure-Activity Relationship
Reg. No./Substance:
0/Bacterial Proteins; 0/Protease Inhibitors; EC 3.4.-/Peptide Hydrolases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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