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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...

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Autores principales: Löwer, Martin, Geppert, Tim, Schneider, Petra, Hoy, Benjamin, Wessler, Silja, Schneider, Gisbert
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2011
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.
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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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