Natural Compounds as Non-Nucleoside Inhibitors of Zika Virus Polymerase through Integration of In Silico and In Vitro Approaches
Autor(a) principal: | |
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Data de Publicação: | 2022 |
Outros Autores: | , , , , , , , , , , , , , , |
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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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) instacron:UNESP |
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) |
repository.mail.fl_str_mv |
|
_version_ |
1808128408160305152 |