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Locking the 150-Cavity Open: In Silico Design and Verification of Influenza Neuraminidase Inhibitors
Neuraminidase (NA) of influenza is a key target for virus infection control and the recently discovered open 150-cavity in group-1 NA provides new opportunity for novel inhibitors design. In this study, we used a combination of theoretical methods including fragment docking, molecular linking and mo...
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/PMC3755005/ https://www.ncbi.nlm.nih.gov/pubmed/24015302 http://dx.doi.org/10.1371/journal.pone.0073344 |
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author | Han, Nanyu Mu, Yuguang |
author_facet | Han, Nanyu Mu, Yuguang |
author_sort | Han, Nanyu |
collection | PubMed |
description | Neuraminidase (NA) of influenza is a key target for virus infection control and the recently discovered open 150-cavity in group-1 NA provides new opportunity for novel inhibitors design. In this study, we used a combination of theoretical methods including fragment docking, molecular linking and molecular dynamics simulations to design ligands that specifically target at the 150-cavity. Through in silico screening of a fragment compound library on the open 150-cavity of NA, a few best scored fragment compounds were selected to link with Zanamivir, one NA-targeting drug. The resultant new ligands may bind both the active site and the 150-cavity of NA simultaneously. Extensive molecular dynamics simulations in explicit solvent were applied to validate the binding between NA and the designed ligands. Moreover, two control systems, a positive control using Zanamivir and a negative control using a low-affinity ligand 3-(p-tolyl) allyl-Neu5Ac2en (ETT, abbreviation reported in the PDB) found in a recent experimental work, were employed to calibrate the simulation method. During the simulations, ETT was observed to detach from NA, on the contrary, both Zanamivir and our designed ligand bind NA firmly. Our study provides a prospective way to design novel inhibitors for controlling the spread of influenza virus. |
format | Online Article Text |
id | pubmed-3755005 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-37550052013-09-06 Locking the 150-Cavity Open: In Silico Design and Verification of Influenza Neuraminidase Inhibitors Han, Nanyu Mu, Yuguang PLoS One Research Article Neuraminidase (NA) of influenza is a key target for virus infection control and the recently discovered open 150-cavity in group-1 NA provides new opportunity for novel inhibitors design. In this study, we used a combination of theoretical methods including fragment docking, molecular linking and molecular dynamics simulations to design ligands that specifically target at the 150-cavity. Through in silico screening of a fragment compound library on the open 150-cavity of NA, a few best scored fragment compounds were selected to link with Zanamivir, one NA-targeting drug. The resultant new ligands may bind both the active site and the 150-cavity of NA simultaneously. Extensive molecular dynamics simulations in explicit solvent were applied to validate the binding between NA and the designed ligands. Moreover, two control systems, a positive control using Zanamivir and a negative control using a low-affinity ligand 3-(p-tolyl) allyl-Neu5Ac2en (ETT, abbreviation reported in the PDB) found in a recent experimental work, were employed to calibrate the simulation method. During the simulations, ETT was observed to detach from NA, on the contrary, both Zanamivir and our designed ligand bind NA firmly. Our study provides a prospective way to design novel inhibitors for controlling the spread of influenza virus. Public Library of Science 2013-08-27 /pmc/articles/PMC3755005/ /pubmed/24015302 http://dx.doi.org/10.1371/journal.pone.0073344 Text en © 2013 Han 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 Han, Nanyu Mu, Yuguang Locking the 150-Cavity Open: In Silico Design and Verification of Influenza Neuraminidase Inhibitors |
title | Locking the 150-Cavity Open: In Silico Design and Verification of Influenza Neuraminidase Inhibitors |
title_full | Locking the 150-Cavity Open: In Silico Design and Verification of Influenza Neuraminidase Inhibitors |
title_fullStr | Locking the 150-Cavity Open: In Silico Design and Verification of Influenza Neuraminidase Inhibitors |
title_full_unstemmed | Locking the 150-Cavity Open: In Silico Design and Verification of Influenza Neuraminidase Inhibitors |
title_short | Locking the 150-Cavity Open: In Silico Design and Verification of Influenza Neuraminidase Inhibitors |
title_sort | locking the 150-cavity open: in silico design and verification of influenza neuraminidase inhibitors |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3755005/ https://www.ncbi.nlm.nih.gov/pubmed/24015302 http://dx.doi.org/10.1371/journal.pone.0073344 |
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