Dabrafenib, idelalisib and nintedanib act as significant allosteric modulator for dengue NS3 protease.

Dengue virus (DENV) encodes a unique protease (NS3/NS2B) essential for its maturation and infectivity and, it has become a key target for anti-viral drug design to treat dengue and other flavivirus related infections. Present investigation established that some of the drug molecules currently used m...

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Autores principales:	R V Sriram Uday, Rajdip Misra, Annaram Harika, Sandip Dolui, Achintya Saha, Uttam Pal, V Ravichandiran, Nakul C Maiti
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/5cdadd6cff564a66ac6bfef33c321c75
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spelling	oai:doaj.org-article:5cdadd6cff564a66ac6bfef33c321c752021-12-02T20:14:42ZDabrafenib, idelalisib and nintedanib act as significant allosteric modulator for dengue NS3 protease.1932-620310.1371/journal.pone.0257206https://doaj.org/article/5cdadd6cff564a66ac6bfef33c321c752021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0257206https://doaj.org/toc/1932-6203Dengue virus (DENV) encodes a unique protease (NS3/NS2B) essential for its maturation and infectivity and, it has become a key target for anti-viral drug design to treat dengue and other flavivirus related infections. Present investigation established that some of the drug molecules currently used mainly in cancer treatment are susceptible to bind non-active site (allosteric site/ cavity) of the NS3 protease enzyme of dengue virus. Computational screening and molecular docking analysis found that dabrafenib, idelalisib and nintedanib can bind at the allosteric site of the enzyme. The binding of the molecules to the allosteric site found to be stabilized via pi-cation and hydrophobic interactions, hydrogen-bond formation and π-stacking interaction with the molecules. Several interacting residues of the enzyme were common in all the five serotypes. However, the interaction/stabilizing forces were not uniformly distributed; the π-stacking was dominated with DENV3 proteases, whereas, a charged/ionic interaction was the major force behind interaction with DENV2 type proteases. In the allosteric cavity of protease from DENV1, the residues Lys73, Lys74, Thr118, Glu120, Val123, Asn152 and Ala164 were involved in active interaction with the three molecules (dabrafenib, idelalisib and nintedanib). Molecular dynamics (MD) analysis further revealed that the molecules on binding to NS3 protease caused significant changes in structural fluctuation and gained enhanced stability. Most importantly, the binding of the molecules effectively perturbed the protein conformation. These changes in the protein conformation and dynamics could generate allosteric modulation and thus may attenuate/alter the NS3 protease functionality and mobility at the active site. Experimental studies may strengthen the notion whether the binding reduce/enhance the catalytic activity of the enzyme, however, it is beyond the scope of this study.R V Sriram UdayRajdip MisraAnnaram HarikaSandip DoluiAchintya SahaUttam PalV RavichandiranNakul C MaitiPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 9, p e0257206 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q R V Sriram Uday Rajdip Misra Annaram Harika Sandip Dolui Achintya Saha Uttam Pal V Ravichandiran Nakul C Maiti Dabrafenib, idelalisib and nintedanib act as significant allosteric modulator for dengue NS3 protease.
description	Dengue virus (DENV) encodes a unique protease (NS3/NS2B) essential for its maturation and infectivity and, it has become a key target for anti-viral drug design to treat dengue and other flavivirus related infections. Present investigation established that some of the drug molecules currently used mainly in cancer treatment are susceptible to bind non-active site (allosteric site/ cavity) of the NS3 protease enzyme of dengue virus. Computational screening and molecular docking analysis found that dabrafenib, idelalisib and nintedanib can bind at the allosteric site of the enzyme. The binding of the molecules to the allosteric site found to be stabilized via pi-cation and hydrophobic interactions, hydrogen-bond formation and π-stacking interaction with the molecules. Several interacting residues of the enzyme were common in all the five serotypes. However, the interaction/stabilizing forces were not uniformly distributed; the π-stacking was dominated with DENV3 proteases, whereas, a charged/ionic interaction was the major force behind interaction with DENV2 type proteases. In the allosteric cavity of protease from DENV1, the residues Lys73, Lys74, Thr118, Glu120, Val123, Asn152 and Ala164 were involved in active interaction with the three molecules (dabrafenib, idelalisib and nintedanib). Molecular dynamics (MD) analysis further revealed that the molecules on binding to NS3 protease caused significant changes in structural fluctuation and gained enhanced stability. Most importantly, the binding of the molecules effectively perturbed the protein conformation. These changes in the protein conformation and dynamics could generate allosteric modulation and thus may attenuate/alter the NS3 protease functionality and mobility at the active site. Experimental studies may strengthen the notion whether the binding reduce/enhance the catalytic activity of the enzyme, however, it is beyond the scope of this study.
format	article
author	R V Sriram Uday Rajdip Misra Annaram Harika Sandip Dolui Achintya Saha Uttam Pal V Ravichandiran Nakul C Maiti
author_facet	R V Sriram Uday Rajdip Misra Annaram Harika Sandip Dolui Achintya Saha Uttam Pal V Ravichandiran Nakul C Maiti
author_sort	R V Sriram Uday
title	Dabrafenib, idelalisib and nintedanib act as significant allosteric modulator for dengue NS3 protease.
title_short	Dabrafenib, idelalisib and nintedanib act as significant allosteric modulator for dengue NS3 protease.
title_full	Dabrafenib, idelalisib and nintedanib act as significant allosteric modulator for dengue NS3 protease.
title_fullStr	Dabrafenib, idelalisib and nintedanib act as significant allosteric modulator for dengue NS3 protease.
title_full_unstemmed	Dabrafenib, idelalisib and nintedanib act as significant allosteric modulator for dengue NS3 protease.
title_sort	dabrafenib, idelalisib and nintedanib act as significant allosteric modulator for dengue ns3 protease.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/5cdadd6cff564a66ac6bfef33c321c75
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Dabrafenib, idelalisib and nintedanib act as significant allosteric modulator for dengue NS3 protease.

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