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 LöwerGND, Tim Geppert, Petra Schneider, Benjamin Hoy, Silja WeßlerORCiDGND, Gisbert SchneiderORCiDGND |
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URN: | urn:nbn:de:hebis:30-114697 |
DOI: | https://doi.org/10.1371/journal.pone.0017986 |
ISSN: | 1932-6203 |
Pubmed Id: | https://pubmed.ncbi.nlm.nih.gov/21483848 |
Parent Title (English): | PLoS One |
Document Type: | Article |
Language: | English |
Date of Publication (online): | 2011/03/31 |
Date of first Publication: | 2011/03/31 |
Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
Release Date: | 2011/09/06 |
Volume: | 6 |
Issue: | (3): e17986 |
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, Chemie und Pharmazie / Biochemie und Chemie |
Dewey Decimal Classification: | 5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie |
Sammlungen: | Universitätspublikationen |
Sammlung Biologie / Sondersammelgebiets-Volltexte | |
Licence (German): | Creative Commons - Namensnennung 3.0 |