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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...

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Autores principales: Han, Nanyu, Mu, Yuguang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
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.
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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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