Inhibitors of Helicobacter pylori protease HtrA found by "virtual ligand" screening combat bacterial invasion of epithelia

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 in
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.
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Metadaten
Author:Martin Löwer, Tim Geppert, Petra Schneider, Benjamin Hoy, Silja Weßler, Gisbert Schneider
URN:urn:nbn:de:hebis:30-114697
DOI:http://dx.doi.org/10.1371/journal.pone.0017986
ISSN:1932-6203
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=21483848
Parent Title (English):PLoS one
Document Type:Article
Language:English
Date of Publication (online):2011/09/06
Year of first Publication:2011
Publishing Institution:Univ.-Bibliothek Frankfurt am Main
Release Date:2011/09/06
Note:
Copyright: © 2011 Löwer et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Source:PLoS ONE 6(3): e17986. doi: 10.1371/journal.pone.0017986
HeBIS PPN:276040198
Institutes:Biochemie und Chemie
Dewey Decimal Classification:570 Biowissenschaften; Biologie
Sammlungen:Universitätspublikationen
Sondersammelgebiets-Volltexte
Licence (German):License LogoCreative Commons - Namensnennung 3.0

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