Toward wide-spectrum antivirals against coronaviruses: Molecular characterization of SARS-CoV-2 NSP13 helicase inhibitors

Autores
Perez Lemus, Gustavo R.; Menéndez, Cintia Anabella; Alvarado, Walter; Byléhn, Fabian; de Pablo, Juan J.
Año de publicación
2022
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
To date, effective therapeutic treatments that confer strong attenuation against coronaviruses (CoVs) remain elusive. Among potential drug targets, the helicase of CoVs is attractive due to its sequence conservation and indispensability. We rely on atomistic molecular dynamics simulations to explore the structural coordination and dynamics associated with the SARS-CoV-2 Nsp13 apo enzyme, as well as their complexes with natural ligands. A complex communication network is revealed among the five domains of Nsp13, which is differentially activated because of the presence of the ligands, as shown by shear strain analysis, principal components analysis, dynamical cross-correlation matrix analysis, and water transport analysis. The binding free energy and the corresponding mechanism of action are presented for three small molecules that were shown to be efficient inhibitors of the previous SARS-CoV Nsp13 enzyme. Together, our findings provide critical fresh insights for rational design of broad-spectrum antivirals against CoVs.
Fil: Perez Lemus, Gustavo R.. University of Chicago; Estados Unidos
Fil: Menéndez, Cintia Anabella. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina
Fil: Alvarado, Walter. University of Chicago; Estados Unidos
Fil: Byléhn, Fabian. University of Chicago; Estados Unidos
Fil: de Pablo, Juan J.. University of Chicago; Estados Unidos
Materia
SARS-CoV-2
NSP13
antivirals
MD simulations
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/204359
Acceder
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network_name_str CONICET Digital (CONICET)
spelling Toward wide-spectrum antivirals against coronaviruses: Molecular characterization of SARS-CoV-2 NSP13 helicase inhibitorsPerez Lemus, Gustavo R.Menéndez, Cintia AnabellaAlvarado, WalterByléhn, Fabiande Pablo, Juan J.SARS-CoV-2NSP13antiviralsMD simulationshttps://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1To date, effective therapeutic treatments that confer strong attenuation against coronaviruses (CoVs) remain elusive. Among potential drug targets, the helicase of CoVs is attractive due to its sequence conservation and indispensability. We rely on atomistic molecular dynamics simulations to explore the structural coordination and dynamics associated with the SARS-CoV-2 Nsp13 apo enzyme, as well as their complexes with natural ligands. A complex communication network is revealed among the five domains of Nsp13, which is differentially activated because of the presence of the ligands, as shown by shear strain analysis, principal components analysis, dynamical cross-correlation matrix analysis, and water transport analysis. The binding free energy and the corresponding mechanism of action are presented for three small molecules that were shown to be efficient inhibitors of the previous SARS-CoV Nsp13 enzyme. Together, our findings provide critical fresh insights for rational design of broad-spectrum antivirals against CoVs.Fil: Perez Lemus, Gustavo R.. University of Chicago; Estados UnidosFil: Menéndez, Cintia Anabella. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; ArgentinaFil: Alvarado, Walter. University of Chicago; Estados UnidosFil: Byléhn, Fabian. University of Chicago; Estados UnidosFil: de Pablo, Juan J.. University of Chicago; Estados UnidosScience Advances is the American Association for the Advancement of Science2022-01-07info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/204359Perez Lemus, Gustavo R.; Menéndez, Cintia Anabella; Alvarado, Walter; Byléhn, Fabian; de Pablo, Juan J.; Toward wide-spectrum antivirals against coronaviruses: Molecular characterization of SARS-CoV-2 NSP13 helicase inhibitors; Science Advances is the American Association for the Advancement of Science; Science Advances; 8; 1; 7-1-2022; 1-122375-2548CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.science.org/doi/10.1126/sciadv.abj4526info:eu-repo/semantics/altIdentifier/doi/10.1126/sciadv.abj4526info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T14:22:43Zoai:ri.conicet.gov.ar:11336/204359instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-15 14:22:44.12CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Toward wide-spectrum antivirals against coronaviruses: Molecular characterization of SARS-CoV-2 NSP13 helicase inhibitors
title Toward wide-spectrum antivirals against coronaviruses: Molecular characterization of SARS-CoV-2 NSP13 helicase inhibitors
spellingShingle Toward wide-spectrum antivirals against coronaviruses: Molecular characterization of SARS-CoV-2 NSP13 helicase inhibitors
Perez Lemus, Gustavo R.
SARS-CoV-2
NSP13
antivirals
MD simulations
title_short Toward wide-spectrum antivirals against coronaviruses: Molecular characterization of SARS-CoV-2 NSP13 helicase inhibitors
title_full Toward wide-spectrum antivirals against coronaviruses: Molecular characterization of SARS-CoV-2 NSP13 helicase inhibitors
title_fullStr Toward wide-spectrum antivirals against coronaviruses: Molecular characterization of SARS-CoV-2 NSP13 helicase inhibitors
title_full_unstemmed Toward wide-spectrum antivirals against coronaviruses: Molecular characterization of SARS-CoV-2 NSP13 helicase inhibitors
title_sort Toward wide-spectrum antivirals against coronaviruses: Molecular characterization of SARS-CoV-2 NSP13 helicase inhibitors
dc.creator.none.fl_str_mv Perez Lemus, Gustavo R.
Menéndez, Cintia Anabella
Alvarado, Walter
Byléhn, Fabian
de Pablo, Juan J.
author Perez Lemus, Gustavo R.
author_facet Perez Lemus, Gustavo R.
Menéndez, Cintia Anabella
Alvarado, Walter
Byléhn, Fabian
de Pablo, Juan J.
author_role author
author2 Menéndez, Cintia Anabella
Alvarado, Walter
Byléhn, Fabian
de Pablo, Juan J.
author2_role author
author
author
author
dc.subject.none.fl_str_mv SARS-CoV-2
NSP13
antivirals
MD simulations
topic SARS-CoV-2
NSP13
antivirals
MD simulations
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv To date, effective therapeutic treatments that confer strong attenuation against coronaviruses (CoVs) remain elusive. Among potential drug targets, the helicase of CoVs is attractive due to its sequence conservation and indispensability. We rely on atomistic molecular dynamics simulations to explore the structural coordination and dynamics associated with the SARS-CoV-2 Nsp13 apo enzyme, as well as their complexes with natural ligands. A complex communication network is revealed among the five domains of Nsp13, which is differentially activated because of the presence of the ligands, as shown by shear strain analysis, principal components analysis, dynamical cross-correlation matrix analysis, and water transport analysis. The binding free energy and the corresponding mechanism of action are presented for three small molecules that were shown to be efficient inhibitors of the previous SARS-CoV Nsp13 enzyme. Together, our findings provide critical fresh insights for rational design of broad-spectrum antivirals against CoVs.
Fil: Perez Lemus, Gustavo R.. University of Chicago; Estados Unidos
Fil: Menéndez, Cintia Anabella. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina
Fil: Alvarado, Walter. University of Chicago; Estados Unidos
Fil: Byléhn, Fabian. University of Chicago; Estados Unidos
Fil: de Pablo, Juan J.. University of Chicago; Estados Unidos
description To date, effective therapeutic treatments that confer strong attenuation against coronaviruses (CoVs) remain elusive. Among potential drug targets, the helicase of CoVs is attractive due to its sequence conservation and indispensability. We rely on atomistic molecular dynamics simulations to explore the structural coordination and dynamics associated with the SARS-CoV-2 Nsp13 apo enzyme, as well as their complexes with natural ligands. A complex communication network is revealed among the five domains of Nsp13, which is differentially activated because of the presence of the ligands, as shown by shear strain analysis, principal components analysis, dynamical cross-correlation matrix analysis, and water transport analysis. The binding free energy and the corresponding mechanism of action are presented for three small molecules that were shown to be efficient inhibitors of the previous SARS-CoV Nsp13 enzyme. Together, our findings provide critical fresh insights for rational design of broad-spectrum antivirals against CoVs.
publishDate 2022
dc.date.none.fl_str_mv 2022-01-07
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/204359
Perez Lemus, Gustavo R.; Menéndez, Cintia Anabella; Alvarado, Walter; Byléhn, Fabian; de Pablo, Juan J.; Toward wide-spectrum antivirals against coronaviruses: Molecular characterization of SARS-CoV-2 NSP13 helicase inhibitors; Science Advances is the American Association for the Advancement of Science; Science Advances; 8; 1; 7-1-2022; 1-12
2375-2548
CONICET Digital
CONICET
url http://hdl.handle.net/11336/204359
identifier_str_mv Perez Lemus, Gustavo R.; Menéndez, Cintia Anabella; Alvarado, Walter; Byléhn, Fabian; de Pablo, Juan J.; Toward wide-spectrum antivirals against coronaviruses: Molecular characterization of SARS-CoV-2 NSP13 helicase inhibitors; Science Advances is the American Association for the Advancement of Science; Science Advances; 8; 1; 7-1-2022; 1-12
2375-2548
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.science.org/doi/10.1126/sciadv.abj4526
info:eu-repo/semantics/altIdentifier/doi/10.1126/sciadv.abj4526
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Science Advances is the American Association for the Advancement of Science
publisher.none.fl_str_mv Science Advances is the American Association for the Advancement of Science
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
_version_ 1846082628017455104
score 13.22299

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