In Vitro Evaluation of Novel Inhibitors against the NS2B-NS3 Protease of Dengue Fever Virus Type 4

The discovery of potent therapeutic compounds against dengue virus is urgently needed. The NS2B-NS3 protease (NS2B-NS3(pro)) of dengue fever virus carries out all enzymatic activities needed for polyprotein processing and is considered to be amenable to antiviral inhibition by analogy. Virtual scree...

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Autores principales: Nguyen, Thi Thanh Hanh, Lee, Sun, Wang, Hsi-Kai, Chen, Hsin-Yen, Wu, Ying-Ta, Lin, Simon C., Kim, Do-Won, Kim, Doman
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2013
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6269914/
https://www.ncbi.nlm.nih.gov/pubmed/24352016
http://dx.doi.org/10.3390/molecules181215600
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author Nguyen, Thi Thanh Hanh
Lee, Sun
Wang, Hsi-Kai
Chen, Hsin-Yen
Wu, Ying-Ta
Lin, Simon C.
Kim, Do-Won
Kim, Doman
author_facet Nguyen, Thi Thanh Hanh
Lee, Sun
Wang, Hsi-Kai
Chen, Hsin-Yen
Wu, Ying-Ta
Lin, Simon C.
Kim, Do-Won
Kim, Doman
author_sort Nguyen, Thi Thanh Hanh
collection PubMed
description The discovery of potent therapeutic compounds against dengue virus is urgently needed. The NS2B-NS3 protease (NS2B-NS3(pro)) of dengue fever virus carries out all enzymatic activities needed for polyprotein processing and is considered to be amenable to antiviral inhibition by analogy. Virtual screening of 300,000 compounds using Autodock 3 on the GVSS platform was conducted to identify novel inhibitors against the NS2B-NS3(pro). Thirty-six compounds were selected for in vitro assay against NS2B-NS3(pro) expressed in Pichia pastoris. Seven novel compounds were identified as inhibitors with IC(50) values of 3.9 ± 0.6–86.7 ± 3.6 μM. Three strong NS2B-NS3(pro) inhibitors were further confirmed as competitive inhibitors with K(i) values of 4.0 ± 0.4, 4.9 ± 0.3, and 3.4 ± 0.1 μM, respectively. Hydrophobic and hydrogen bond interactions between amino acid residues in the NS3(pro) active site with inhibition compounds were also identified.
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spelling pubmed-62699142018-12-20 In Vitro Evaluation of Novel Inhibitors against the NS2B-NS3 Protease of Dengue Fever Virus Type 4 Nguyen, Thi Thanh Hanh Lee, Sun Wang, Hsi-Kai Chen, Hsin-Yen Wu, Ying-Ta Lin, Simon C. Kim, Do-Won Kim, Doman Molecules Article The discovery of potent therapeutic compounds against dengue virus is urgently needed. The NS2B-NS3 protease (NS2B-NS3(pro)) of dengue fever virus carries out all enzymatic activities needed for polyprotein processing and is considered to be amenable to antiviral inhibition by analogy. Virtual screening of 300,000 compounds using Autodock 3 on the GVSS platform was conducted to identify novel inhibitors against the NS2B-NS3(pro). Thirty-six compounds were selected for in vitro assay against NS2B-NS3(pro) expressed in Pichia pastoris. Seven novel compounds were identified as inhibitors with IC(50) values of 3.9 ± 0.6–86.7 ± 3.6 μM. Three strong NS2B-NS3(pro) inhibitors were further confirmed as competitive inhibitors with K(i) values of 4.0 ± 0.4, 4.9 ± 0.3, and 3.4 ± 0.1 μM, respectively. Hydrophobic and hydrogen bond interactions between amino acid residues in the NS3(pro) active site with inhibition compounds were also identified. MDPI 2013-12-13 /pmc/articles/PMC6269914/ /pubmed/24352016 http://dx.doi.org/10.3390/molecules181215600 Text en © 2013 by the authors; licensee MDPI, Basel, Switzerland. http://creativecommons.org/licenses/by/3.0/ This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).
spellingShingle Article
Nguyen, Thi Thanh Hanh
Lee, Sun
Wang, Hsi-Kai
Chen, Hsin-Yen
Wu, Ying-Ta
Lin, Simon C.
Kim, Do-Won
Kim, Doman
In Vitro Evaluation of Novel Inhibitors against the NS2B-NS3 Protease of Dengue Fever Virus Type 4
title In Vitro Evaluation of Novel Inhibitors against the NS2B-NS3 Protease of Dengue Fever Virus Type 4
title_full In Vitro Evaluation of Novel Inhibitors against the NS2B-NS3 Protease of Dengue Fever Virus Type 4
title_fullStr In Vitro Evaluation of Novel Inhibitors against the NS2B-NS3 Protease of Dengue Fever Virus Type 4
title_full_unstemmed In Vitro Evaluation of Novel Inhibitors against the NS2B-NS3 Protease of Dengue Fever Virus Type 4
title_short In Vitro Evaluation of Novel Inhibitors against the NS2B-NS3 Protease of Dengue Fever Virus Type 4
title_sort in vitro evaluation of novel inhibitors against the ns2b-ns3 protease of dengue fever virus type 4
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6269914/
https://www.ncbi.nlm.nih.gov/pubmed/24352016
http://dx.doi.org/10.3390/molecules181215600
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