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Mechanistic insights into the Japanese encephalitis virus RNA dependent RNA polymerase protein inhibition by bioflavonoids from Azadirachta indica

Japanese encephalitis (JE) virus is a flavivirus causing encephalitis causing neurological damage. RNA-dependent-RNA-polymerase (RdRp) is responsible for genome replication making it excellent anti-viral target. In this study, the crystal structure of JE RdRp (jRdRp) and bioflavonoids reported in Az...

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Autores principales: Dwivedi, Vivek Dhar, Singh, Ankita, El-Kafraway, Sherif Aly, Alandijany, Thamir A., Faizo, Arwa A., Bajrai, Leena Hussein, Kamal, Mohammad Amjad, Azhar, Esam Ibraheem
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8437980/
https://www.ncbi.nlm.nih.gov/pubmed/34518560
http://dx.doi.org/10.1038/s41598-021-96917-0
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author Dwivedi, Vivek Dhar
Singh, Ankita
El-Kafraway, Sherif Aly
Alandijany, Thamir A.
Faizo, Arwa A.
Bajrai, Leena Hussein
Kamal, Mohammad Amjad
Azhar, Esam Ibraheem
author_facet Dwivedi, Vivek Dhar
Singh, Ankita
El-Kafraway, Sherif Aly
Alandijany, Thamir A.
Faizo, Arwa A.
Bajrai, Leena Hussein
Kamal, Mohammad Amjad
Azhar, Esam Ibraheem
author_sort Dwivedi, Vivek Dhar
collection PubMed
description Japanese encephalitis (JE) virus is a flavivirus causing encephalitis causing neurological damage. RNA-dependent-RNA-polymerase (RdRp) is responsible for genome replication making it excellent anti-viral target. In this study, the crystal structure of JE RdRp (jRdRp) and bioflavonoids reported in Azadirachta indica were retrieved from specific databases. Structure-based virtual screening was employed using MTiOpenScreen server and top four compounds selected with the most negative docking scores. Conformations were redocked using AutoDock Vina; these complexes showed mechanistic interactions with Arg(474), Gly(605), Asp(668), and Trp(800) residues in the active site of jRdRp, i.e., guanosine-5′-triphosphate. Furthermore, 100 ns classical molecular dynamics simulation and binding free energy calculation showed stability of docked bioflavonoids in the active jRdRp pocket and significant contribution of van-der-Waals interactions for docked complex stability during simulation. Therefore, this study predicted the anti-viral activity of Gedunin, Nimbolide, Ohchinin acetate, and Kulactone against jRdRp and can be considered for further antiviral drug development.
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spelling pubmed-84379802021-09-15 Mechanistic insights into the Japanese encephalitis virus RNA dependent RNA polymerase protein inhibition by bioflavonoids from Azadirachta indica Dwivedi, Vivek Dhar Singh, Ankita El-Kafraway, Sherif Aly Alandijany, Thamir A. Faizo, Arwa A. Bajrai, Leena Hussein Kamal, Mohammad Amjad Azhar, Esam Ibraheem Sci Rep Article Japanese encephalitis (JE) virus is a flavivirus causing encephalitis causing neurological damage. RNA-dependent-RNA-polymerase (RdRp) is responsible for genome replication making it excellent anti-viral target. In this study, the crystal structure of JE RdRp (jRdRp) and bioflavonoids reported in Azadirachta indica were retrieved from specific databases. Structure-based virtual screening was employed using MTiOpenScreen server and top four compounds selected with the most negative docking scores. Conformations were redocked using AutoDock Vina; these complexes showed mechanistic interactions with Arg(474), Gly(605), Asp(668), and Trp(800) residues in the active site of jRdRp, i.e., guanosine-5′-triphosphate. Furthermore, 100 ns classical molecular dynamics simulation and binding free energy calculation showed stability of docked bioflavonoids in the active jRdRp pocket and significant contribution of van-der-Waals interactions for docked complex stability during simulation. Therefore, this study predicted the anti-viral activity of Gedunin, Nimbolide, Ohchinin acetate, and Kulactone against jRdRp and can be considered for further antiviral drug development. Nature Publishing Group UK 2021-09-13 /pmc/articles/PMC8437980/ /pubmed/34518560 http://dx.doi.org/10.1038/s41598-021-96917-0 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Dwivedi, Vivek Dhar
Singh, Ankita
El-Kafraway, Sherif Aly
Alandijany, Thamir A.
Faizo, Arwa A.
Bajrai, Leena Hussein
Kamal, Mohammad Amjad
Azhar, Esam Ibraheem
Mechanistic insights into the Japanese encephalitis virus RNA dependent RNA polymerase protein inhibition by bioflavonoids from Azadirachta indica
title Mechanistic insights into the Japanese encephalitis virus RNA dependent RNA polymerase protein inhibition by bioflavonoids from Azadirachta indica
title_full Mechanistic insights into the Japanese encephalitis virus RNA dependent RNA polymerase protein inhibition by bioflavonoids from Azadirachta indica
title_fullStr Mechanistic insights into the Japanese encephalitis virus RNA dependent RNA polymerase protein inhibition by bioflavonoids from Azadirachta indica
title_full_unstemmed Mechanistic insights into the Japanese encephalitis virus RNA dependent RNA polymerase protein inhibition by bioflavonoids from Azadirachta indica
title_short Mechanistic insights into the Japanese encephalitis virus RNA dependent RNA polymerase protein inhibition by bioflavonoids from Azadirachta indica
title_sort mechanistic insights into the japanese encephalitis virus rna dependent rna polymerase protein inhibition by bioflavonoids from azadirachta indica
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8437980/
https://www.ncbi.nlm.nih.gov/pubmed/34518560
http://dx.doi.org/10.1038/s41598-021-96917-0
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