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Zika Virus NS3 Protease Pharmacophore Anchor Model and Drug Discovery

Zika virus (ZIKV) of the flaviviridae family, is the cause of emerging infections characterized by fever, Guillain-Barré syndrome (GBS) in adults and microcephaly in newborns. There exists an urgent unmet clinical need for anti-ZIKV drugs for the treatment of infected individuals. In the current wor...

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Autores principales: Pathak, Nikhil, Kuo, Yi-Ping, Chang, Teng-Yuan, Huang, Chin-Ting, Hung, Hui-Chen, Hsu, John Tsu-An, Yu, Guann-Yi, Yang, Jinn-Moon
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7265434/
https://www.ncbi.nlm.nih.gov/pubmed/32488021
http://dx.doi.org/10.1038/s41598-020-65489-w
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author Pathak, Nikhil
Kuo, Yi-Ping
Chang, Teng-Yuan
Huang, Chin-Ting
Hung, Hui-Chen
Hsu, John Tsu-An
Yu, Guann-Yi
Yang, Jinn-Moon
author_facet Pathak, Nikhil
Kuo, Yi-Ping
Chang, Teng-Yuan
Huang, Chin-Ting
Hung, Hui-Chen
Hsu, John Tsu-An
Yu, Guann-Yi
Yang, Jinn-Moon
author_sort Pathak, Nikhil
collection PubMed
description Zika virus (ZIKV) of the flaviviridae family, is the cause of emerging infections characterized by fever, Guillain-Barré syndrome (GBS) in adults and microcephaly in newborns. There exists an urgent unmet clinical need for anti-ZIKV drugs for the treatment of infected individuals. In the current work, we aimed at the promising virus drug target, ZIKV NS3 protease and constructed a Pharmacophore Anchor (PA) model for the active site. The PA model reveals a total of 12 anchors (E, H, V) mapped across the active site subpockets. We further identified five of these anchors to be critical core anchors (CEH1, CH3, CH7, CV1, CV3) conserved across flaviviral proteases. The ZIKV protease PA model was then applied in anchor-enhanced virtual screening yielding 14 potential antiviral candidates, which were tested by in vitro assays. We discovered FDA drugs Asunaprevir and Simeprevir to have potent anti-ZIKV activities with EC(50) values 4.7 µM and 0.4 µM, inhibiting the viral protease with IC(50) values 6.0 µM and 2.6 µM respectively. Additionally, the PA model anchors aided in the exploration of inhibitor binding mechanisms. In conclusion, our PA model serves as a promising guide map for ZIKV protease targeted drug discovery and the identified ‘previr’ FDA drugs are promising for anti-ZIKV treatments.
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spelling pubmed-72654342020-06-05 Zika Virus NS3 Protease Pharmacophore Anchor Model and Drug Discovery Pathak, Nikhil Kuo, Yi-Ping Chang, Teng-Yuan Huang, Chin-Ting Hung, Hui-Chen Hsu, John Tsu-An Yu, Guann-Yi Yang, Jinn-Moon Sci Rep Article Zika virus (ZIKV) of the flaviviridae family, is the cause of emerging infections characterized by fever, Guillain-Barré syndrome (GBS) in adults and microcephaly in newborns. There exists an urgent unmet clinical need for anti-ZIKV drugs for the treatment of infected individuals. In the current work, we aimed at the promising virus drug target, ZIKV NS3 protease and constructed a Pharmacophore Anchor (PA) model for the active site. The PA model reveals a total of 12 anchors (E, H, V) mapped across the active site subpockets. We further identified five of these anchors to be critical core anchors (CEH1, CH3, CH7, CV1, CV3) conserved across flaviviral proteases. The ZIKV protease PA model was then applied in anchor-enhanced virtual screening yielding 14 potential antiviral candidates, which were tested by in vitro assays. We discovered FDA drugs Asunaprevir and Simeprevir to have potent anti-ZIKV activities with EC(50) values 4.7 µM and 0.4 µM, inhibiting the viral protease with IC(50) values 6.0 µM and 2.6 µM respectively. Additionally, the PA model anchors aided in the exploration of inhibitor binding mechanisms. In conclusion, our PA model serves as a promising guide map for ZIKV protease targeted drug discovery and the identified ‘previr’ FDA drugs are promising for anti-ZIKV treatments. Nature Publishing Group UK 2020-06-02 /pmc/articles/PMC7265434/ /pubmed/32488021 http://dx.doi.org/10.1038/s41598-020-65489-w Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Pathak, Nikhil
Kuo, Yi-Ping
Chang, Teng-Yuan
Huang, Chin-Ting
Hung, Hui-Chen
Hsu, John Tsu-An
Yu, Guann-Yi
Yang, Jinn-Moon
Zika Virus NS3 Protease Pharmacophore Anchor Model and Drug Discovery
title Zika Virus NS3 Protease Pharmacophore Anchor Model and Drug Discovery
title_full Zika Virus NS3 Protease Pharmacophore Anchor Model and Drug Discovery
title_fullStr Zika Virus NS3 Protease Pharmacophore Anchor Model and Drug Discovery
title_full_unstemmed Zika Virus NS3 Protease Pharmacophore Anchor Model and Drug Discovery
title_short Zika Virus NS3 Protease Pharmacophore Anchor Model and Drug Discovery
title_sort zika virus ns3 protease pharmacophore anchor model and drug discovery
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7265434/
https://www.ncbi.nlm.nih.gov/pubmed/32488021
http://dx.doi.org/10.1038/s41598-020-65489-w
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