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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-ba...
Autores principales: | , , , , , |
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Formato: | Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3069028/ https://www.ncbi.nlm.nih.gov/pubmed/21483848 http://dx.doi.org/10.1371/journal.pone.0017986 |
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author | Löwer, Martin Geppert, Tim Schneider, Petra Hoy, Benjamin Wessler, Silja Schneider, Gisbert |
author_facet | Löwer, Martin Geppert, Tim Schneider, Petra Hoy, Benjamin Wessler, Silja Schneider, Gisbert |
author_sort | Löwer, Martin |
collection | PubMed |
description | 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. |
format | Text |
id | pubmed-3069028 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-30690282011-04-11 Inhibitors of Helicobacter pylori Protease HtrA Found by ‘Virtual Ligand’ Screening Combat Bacterial Invasion of Epithelia Löwer, Martin Geppert, Tim Schneider, Petra Hoy, Benjamin Wessler, Silja Schneider, Gisbert PLoS One Research Article 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. Public Library of Science 2011-03-31 /pmc/articles/PMC3069028/ /pubmed/21483848 http://dx.doi.org/10.1371/journal.pone.0017986 Text en Löwer et al. http://creativecommons.org/licenses/by/4.0/ 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 properly credited. |
spellingShingle | Research Article Löwer, Martin Geppert, Tim Schneider, Petra Hoy, Benjamin Wessler, Silja Schneider, Gisbert Inhibitors of Helicobacter pylori Protease HtrA Found by ‘Virtual Ligand’ Screening Combat Bacterial Invasion of Epithelia |
title | Inhibitors of Helicobacter pylori Protease HtrA Found by ‘Virtual Ligand’ Screening Combat Bacterial Invasion of Epithelia |
title_full | Inhibitors of Helicobacter pylori Protease HtrA Found by ‘Virtual Ligand’ Screening Combat Bacterial Invasion of Epithelia |
title_fullStr | Inhibitors of Helicobacter pylori Protease HtrA Found by ‘Virtual Ligand’ Screening Combat Bacterial Invasion of Epithelia |
title_full_unstemmed | Inhibitors of Helicobacter pylori Protease HtrA Found by ‘Virtual Ligand’ Screening Combat Bacterial Invasion of Epithelia |
title_short | Inhibitors of Helicobacter pylori Protease HtrA Found by ‘Virtual Ligand’ Screening Combat Bacterial Invasion of Epithelia |
title_sort | inhibitors of helicobacter pylori protease htra found by ‘virtual ligand’ screening combat bacterial invasion of epithelia |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3069028/ https://www.ncbi.nlm.nih.gov/pubmed/21483848 http://dx.doi.org/10.1371/journal.pone.0017986 |
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