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 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.
|Author:||Martin Löwer, Tim Geppert, Petra Schneider, Benjamin Hoy, Silja Weßler, Gisbert Schneider|
|Parent Title (English):||PLoS one|
|Date of Publication (online):||06.09.2011|
|Year of first Publication:||2011|
|Publishing Institution:||Univ.-Bibliothek Frankfurt am Main|
|Source:||PLoS ONE 6(3): e17986. doi: 10.1371/journal.pone.0017986|
|Institutes:||Biochemie und Chemie|
|Dewey Decimal Classification:||570 Biowissenschaften; Biologie|
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.
|Licence (German):||Creative Commons - Namensnennung 3.0|