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Inhibition of Histo-blood Group Antigen Binding as a Novel Strategy to Block Norovirus Infections
Noroviruses (NoVs) are the most important viral pathogens that cause epidemic acute gastroenteritis. NoVs recognize human histo-blood group antigens (HBGAs) as receptors or attachment factors. The elucidation of crystal structures of the HBGA-binding interfaces of a number of human NoVs representing...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3716607/ https://www.ncbi.nlm.nih.gov/pubmed/23894462 http://dx.doi.org/10.1371/journal.pone.0069379 |
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author | Zhang, Xu-Fu Tan, Ming Chhabra, Monica Dai, Ying-Chun Meller, Jarek Jiang, Xi |
author_facet | Zhang, Xu-Fu Tan, Ming Chhabra, Monica Dai, Ying-Chun Meller, Jarek Jiang, Xi |
author_sort | Zhang, Xu-Fu |
collection | PubMed |
description | Noroviruses (NoVs) are the most important viral pathogens that cause epidemic acute gastroenteritis. NoVs recognize human histo-blood group antigens (HBGAs) as receptors or attachment factors. The elucidation of crystal structures of the HBGA-binding interfaces of a number of human NoVs representing different HBGA binding patterns opens a new strategy for the development of antiviral compounds against NoVs through rational drug design and computer-aided virtual screening methods. In this study, docking simulations and virtual screening were used to identify hit compounds targeting the A and B antigens binding sites on the surface of the capsid P protein of a GII.4 NoV (VA387). Following validation by re-docking of the A and B ligands, these structural models and AutoDock suite of programs were used to screen a large drug-like compound library (derived from ZINC library) for inhibitors blocking GII.4 binding to HBGAs. After screening >2 million compounds using multistage protocol, 160 hit compounds with best predicted binding affinities and representing a number of distinct chemical classes have been selected for subsequent experimental validation. Twenty of the 160 compounds were found to be able to block the VA387 P dimers binding to the A and/or B HBGAs at an IC(50)<40.0 µM, with top 5 compounds blocking the HBGA binding at an IC(50)<10.0 µM in both oligosaccharide- and saliva-based blocking assays. Interestingly, 4 of the top-5 compounds shared the basic structure of cyclopenta [a] dimethyl phenanthren, indicating a promising structural template for further improvement by rational design. |
format | Online Article Text |
id | pubmed-3716607 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-37166072013-07-26 Inhibition of Histo-blood Group Antigen Binding as a Novel Strategy to Block Norovirus Infections Zhang, Xu-Fu Tan, Ming Chhabra, Monica Dai, Ying-Chun Meller, Jarek Jiang, Xi PLoS One Research Article Noroviruses (NoVs) are the most important viral pathogens that cause epidemic acute gastroenteritis. NoVs recognize human histo-blood group antigens (HBGAs) as receptors or attachment factors. The elucidation of crystal structures of the HBGA-binding interfaces of a number of human NoVs representing different HBGA binding patterns opens a new strategy for the development of antiviral compounds against NoVs through rational drug design and computer-aided virtual screening methods. In this study, docking simulations and virtual screening were used to identify hit compounds targeting the A and B antigens binding sites on the surface of the capsid P protein of a GII.4 NoV (VA387). Following validation by re-docking of the A and B ligands, these structural models and AutoDock suite of programs were used to screen a large drug-like compound library (derived from ZINC library) for inhibitors blocking GII.4 binding to HBGAs. After screening >2 million compounds using multistage protocol, 160 hit compounds with best predicted binding affinities and representing a number of distinct chemical classes have been selected for subsequent experimental validation. Twenty of the 160 compounds were found to be able to block the VA387 P dimers binding to the A and/or B HBGAs at an IC(50)<40.0 µM, with top 5 compounds blocking the HBGA binding at an IC(50)<10.0 µM in both oligosaccharide- and saliva-based blocking assays. Interestingly, 4 of the top-5 compounds shared the basic structure of cyclopenta [a] dimethyl phenanthren, indicating a promising structural template for further improvement by rational design. Public Library of Science 2013-07-19 /pmc/articles/PMC3716607/ /pubmed/23894462 http://dx.doi.org/10.1371/journal.pone.0069379 Text en © 2013 Zhang 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 Zhang, Xu-Fu Tan, Ming Chhabra, Monica Dai, Ying-Chun Meller, Jarek Jiang, Xi Inhibition of Histo-blood Group Antigen Binding as a Novel Strategy to Block Norovirus Infections |
title | Inhibition of Histo-blood Group Antigen Binding as a Novel Strategy to Block Norovirus Infections |
title_full | Inhibition of Histo-blood Group Antigen Binding as a Novel Strategy to Block Norovirus Infections |
title_fullStr | Inhibition of Histo-blood Group Antigen Binding as a Novel Strategy to Block Norovirus Infections |
title_full_unstemmed | Inhibition of Histo-blood Group Antigen Binding as a Novel Strategy to Block Norovirus Infections |
title_short | Inhibition of Histo-blood Group Antigen Binding as a Novel Strategy to Block Norovirus Infections |
title_sort | inhibition of histo-blood group antigen binding as a novel strategy to block norovirus infections |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3716607/ https://www.ncbi.nlm.nih.gov/pubmed/23894462 http://dx.doi.org/10.1371/journal.pone.0069379 |
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