Natural Compounds as Non-Nucleoside Inhibitors of Zika Virus Polymerase through Integration of In Silico and In Vitro Approaches

Detalhes bibliográficos
Autor(a) principal: Ramos, Paulo Ricardo Pimenta da Silva
Data de Publicação: 2022
Outros Autores: Mottin, Melina, Lima, Caroline Sprengel [UNESP], Assis, Letícia R. [UNESP], de Oliveira, Ketllyn Zagato, Mesquita, Nathalya Cristina de Moraes Roso, Cassani, Natasha Marques, Santos, Igor Andrade, Borba, Joyce Villa Verde Bastos, Fiaia Costa, Vinícius Alexandre, Neves, Bruno Junior, Guido, Rafael Victorio Carvalho, Oliva, Glaucius, Jardim, Ana Carolina Gomes, Regasini, Luis Octávio [UNESP], Andrade, Carolina Horta
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Institucional da UNESP
Texto Completo: http://dx.doi.org/10.3390/ph15121493
http://hdl.handle.net/11449/246535
Resumo: Although the past epidemic of Zika virus (ZIKV) resulted in severe neurological consequences for infected infants and adults, there are still no approved drugs to treat ZIKV infection. In this study, we applied computational approaches to screen an in-house database of 77 natural and semi-synthetic compounds against ZIKV NS5 RNA-dependent RNA-polymerase (NS5 RdRp), an essential protein for viral RNA elongation during the replication process. For this purpose, we integrated computational approaches such as binding-site conservation, chemical space analysis and molecular docking. As a result, we prioritized nine virtual hits for experimental evaluation. Enzymatic assays confirmed that pedalitin and quercetin inhibited ZIKV NS5 RdRp with IC50 values of 4.1 and 0.5 µM, respectively. Moreover, pedalitin also displayed antiviral activity on ZIKV infection with an EC50 of 19.28 µM cell-based assays, with low toxicity in Vero cells (CC50 = 83.66 µM) and selectivity index of 4.34. These results demonstrate the potential of the natural compounds pedalitin and quercetin as candidates for structural optimization studies towards the discovery of new anti-ZIKV drug candidates.
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spelling Natural Compounds as Non-Nucleoside Inhibitors of Zika Virus Polymerase through Integration of In Silico and In Vitro Approachesantiviraldockingdrug discoveryflavonoidnon-nucleoside inhibitorNS5 RdRp proteinpedalitinpolymerasequercetinZika virusAlthough the past epidemic of Zika virus (ZIKV) resulted in severe neurological consequences for infected infants and adults, there are still no approved drugs to treat ZIKV infection. In this study, we applied computational approaches to screen an in-house database of 77 natural and semi-synthetic compounds against ZIKV NS5 RNA-dependent RNA-polymerase (NS5 RdRp), an essential protein for viral RNA elongation during the replication process. For this purpose, we integrated computational approaches such as binding-site conservation, chemical space analysis and molecular docking. As a result, we prioritized nine virtual hits for experimental evaluation. Enzymatic assays confirmed that pedalitin and quercetin inhibited ZIKV NS5 RdRp with IC50 values of 4.1 and 0.5 µM, respectively. Moreover, pedalitin also displayed antiviral activity on ZIKV infection with an EC50 of 19.28 µM cell-based assays, with low toxicity in Vero cells (CC50 = 83.66 µM) and selectivity index of 4.34. These results demonstrate the potential of the natural compounds pedalitin and quercetin as candidates for structural optimization studies towards the discovery of new anti-ZIKV drug candidates.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Fundação de Amparo à Pesquisa do Estado de GoiásFundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG)LabMol-Laboratory for Molecular Modeling and Drug Design Faculdade de Farmácia Universidade Federal de GoiásLaboratory of Antibiotics and Chemotherapeutics (LAC) Institute of Biosciences Humanities and Exact Sciences São Paulo State University (Unesp)LaBEFar-Laboratory of Structural Biology and Drugs Institute of Physics of São Carlos University of São PauloLaboratory of Antiviral Research Institute of Biomedical Science Federal University of UberlandiaLaboratory of Antibiotics and Chemotherapeutics (LAC) Institute of Biosciences Humanities and Exact Sciences São Paulo State University (Unesp)CNPq: 142495/2020-4CNPq: 150759/2017-7FAPESP: 2013/07600-3FAPESP: 2014/18330-0Fundação de Amparo à Pesquisa do Estado de Goiás: 20171026700006FAPESP: 2018/15083-2FAPESP: 2019/01762-8FAPESP: 2020/12904-5Fundação de Amparo à Pesquisa do Estado de Goiás: 202010267000272FAPEMIG: APQ-01487-22FAPEMIG: APQ-03385–18Universidade Federal de Goiás (UFG)Universidade Estadual Paulista (UNESP)Universidade de São Paulo (USP)Universidade Federal de Uberlândia (UFU)Ramos, Paulo Ricardo Pimenta da SilvaMottin, MelinaLima, Caroline Sprengel [UNESP]Assis, Letícia R. [UNESP]de Oliveira, Ketllyn ZagatoMesquita, Nathalya Cristina de Moraes RosoCassani, Natasha MarquesSantos, Igor AndradeBorba, Joyce Villa Verde BastosFiaia Costa, Vinícius AlexandreNeves, Bruno JuniorGuido, Rafael Victorio CarvalhoOliva, GlauciusJardim, Ana Carolina GomesRegasini, Luis Octávio [UNESP]Andrade, Carolina Horta2023-07-29T12:43:42Z2023-07-29T12:43:42Z2022-12-01info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://dx.doi.org/10.3390/ph15121493Pharmaceuticals, v. 15, n. 12, 2022.1424-8247http://hdl.handle.net/11449/24653510.3390/ph151214932-s2.0-85144673468Scopusreponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengPharmaceuticalsinfo:eu-repo/semantics/openAccess2023-07-29T12:43:42Zoai:repositorio.unesp.br:11449/246535Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462024-08-05T14:43:39.873696Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false
dc.title.none.fl_str_mv Natural Compounds as Non-Nucleoside Inhibitors of Zika Virus Polymerase through Integration of In Silico and In Vitro Approaches
title Natural Compounds as Non-Nucleoside Inhibitors of Zika Virus Polymerase through Integration of In Silico and In Vitro Approaches
spellingShingle Natural Compounds as Non-Nucleoside Inhibitors of Zika Virus Polymerase through Integration of In Silico and In Vitro Approaches
Ramos, Paulo Ricardo Pimenta da Silva
antiviral
docking
drug discovery
flavonoid
non-nucleoside inhibitor
NS5 RdRp protein
pedalitin
polymerase
quercetin
Zika virus
title_short Natural Compounds as Non-Nucleoside Inhibitors of Zika Virus Polymerase through Integration of In Silico and In Vitro Approaches
title_full Natural Compounds as Non-Nucleoside Inhibitors of Zika Virus Polymerase through Integration of In Silico and In Vitro Approaches
title_fullStr Natural Compounds as Non-Nucleoside Inhibitors of Zika Virus Polymerase through Integration of In Silico and In Vitro Approaches
title_full_unstemmed Natural Compounds as Non-Nucleoside Inhibitors of Zika Virus Polymerase through Integration of In Silico and In Vitro Approaches
title_sort Natural Compounds as Non-Nucleoside Inhibitors of Zika Virus Polymerase through Integration of In Silico and In Vitro Approaches
author Ramos, Paulo Ricardo Pimenta da Silva
author_facet Ramos, Paulo Ricardo Pimenta da Silva
Mottin, Melina
Lima, Caroline Sprengel [UNESP]
Assis, Letícia R. [UNESP]
de Oliveira, Ketllyn Zagato
Mesquita, Nathalya Cristina de Moraes Roso
Cassani, Natasha Marques
Santos, Igor Andrade
Borba, Joyce Villa Verde Bastos
Fiaia Costa, Vinícius Alexandre
Neves, Bruno Junior
Guido, Rafael Victorio Carvalho
Oliva, Glaucius
Jardim, Ana Carolina Gomes
Regasini, Luis Octávio [UNESP]
Andrade, Carolina Horta
author_role author
author2 Mottin, Melina
Lima, Caroline Sprengel [UNESP]
Assis, Letícia R. [UNESP]
de Oliveira, Ketllyn Zagato
Mesquita, Nathalya Cristina de Moraes Roso
Cassani, Natasha Marques
Santos, Igor Andrade
Borba, Joyce Villa Verde Bastos
Fiaia Costa, Vinícius Alexandre
Neves, Bruno Junior
Guido, Rafael Victorio Carvalho
Oliva, Glaucius
Jardim, Ana Carolina Gomes
Regasini, Luis Octávio [UNESP]
Andrade, Carolina Horta
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universidade Federal de Goiás (UFG)
Universidade Estadual Paulista (UNESP)
Universidade de São Paulo (USP)
Universidade Federal de Uberlândia (UFU)
dc.contributor.author.fl_str_mv Ramos, Paulo Ricardo Pimenta da Silva
Mottin, Melina
Lima, Caroline Sprengel [UNESP]
Assis, Letícia R. [UNESP]
de Oliveira, Ketllyn Zagato
Mesquita, Nathalya Cristina de Moraes Roso
Cassani, Natasha Marques
Santos, Igor Andrade
Borba, Joyce Villa Verde Bastos
Fiaia Costa, Vinícius Alexandre
Neves, Bruno Junior
Guido, Rafael Victorio Carvalho
Oliva, Glaucius
Jardim, Ana Carolina Gomes
Regasini, Luis Octávio [UNESP]
Andrade, Carolina Horta
dc.subject.por.fl_str_mv antiviral
docking
drug discovery
flavonoid
non-nucleoside inhibitor
NS5 RdRp protein
pedalitin
polymerase
quercetin
Zika virus
topic antiviral
docking
drug discovery
flavonoid
non-nucleoside inhibitor
NS5 RdRp protein
pedalitin
polymerase
quercetin
Zika virus
description Although the past epidemic of Zika virus (ZIKV) resulted in severe neurological consequences for infected infants and adults, there are still no approved drugs to treat ZIKV infection. In this study, we applied computational approaches to screen an in-house database of 77 natural and semi-synthetic compounds against ZIKV NS5 RNA-dependent RNA-polymerase (NS5 RdRp), an essential protein for viral RNA elongation during the replication process. For this purpose, we integrated computational approaches such as binding-site conservation, chemical space analysis and molecular docking. As a result, we prioritized nine virtual hits for experimental evaluation. Enzymatic assays confirmed that pedalitin and quercetin inhibited ZIKV NS5 RdRp with IC50 values of 4.1 and 0.5 µM, respectively. Moreover, pedalitin also displayed antiviral activity on ZIKV infection with an EC50 of 19.28 µM cell-based assays, with low toxicity in Vero cells (CC50 = 83.66 µM) and selectivity index of 4.34. These results demonstrate the potential of the natural compounds pedalitin and quercetin as candidates for structural optimization studies towards the discovery of new anti-ZIKV drug candidates.
publishDate 2022
dc.date.none.fl_str_mv 2022-12-01
2023-07-29T12:43:42Z
2023-07-29T12:43:42Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://dx.doi.org/10.3390/ph15121493
Pharmaceuticals, v. 15, n. 12, 2022.
1424-8247
http://hdl.handle.net/11449/246535
10.3390/ph15121493
2-s2.0-85144673468
url http://dx.doi.org/10.3390/ph15121493
http://hdl.handle.net/11449/246535
identifier_str_mv Pharmaceuticals, v. 15, n. 12, 2022.
1424-8247
10.3390/ph15121493
2-s2.0-85144673468
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv Pharmaceuticals
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.source.none.fl_str_mv Scopus
reponame:Repositório Institucional da UNESP
instname:Universidade Estadual Paulista (UNESP)
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instname_str Universidade Estadual Paulista (UNESP)
instacron_str UNESP
institution UNESP
reponame_str Repositório Institucional da UNESP
collection Repositório Institucional da UNESP
repository.name.fl_str_mv Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)
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