Drug repurposing screening validated by experimental assays identifies two clinical drugs targeting SARS-CoV-2 main protease

Autores
Prada Gori, Denis Nihuel; Ruatta Merke, Santiago Matías; Fló, Martín; Alberca, Lucas Nicolás; Bellera, Carolina Leticia; Park, Soonju; Heo, Jinyeong; Lee, Honggun; Park, Kyu Ho Paul; Otto Pritsch; Shum, David; Comini, Marcelo A.; Talevi, Alan
Año de publicación
2023
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The COVID-19 pandemic prompted several drug repositioning initiatives with the aim to rapidly deliver pharmacological candidates able to reduce SARS-CoV-2 dissemination and mortality. A major issue shared by many of the in silico studies addressing the discovery of compounds or drugs targeting SARS-CoV-2 molecules is that they lacked experimental validation of the results. Here we present a computer-aided drug-repositioning campaign against the indispensable SARS-CoV-2 main protease (MPro or 3CLPro) that involved the development of ligand-based ensemble models and the experimental testing of a small subset of the identified hits. The search method explored random subspaces of molecular descriptors to obtain linear classifiers. The best models were then combined by selective ensemble learning to improve their predictive power. Both the individual models and the ensembles were validated by retrospective screening, and later used to screen the DrugBank, Drug Repurposing Hub and Sweetlead libraries for potential inhibitors of MPro. From the 4 in silico hits assayed, atpenin and tinostamustine inhibited MPro (IC50 1 µM and 4 μM, respectively) but not the papain-like protease of SARS-CoV-2 (drugs tested at 25 μM). Preliminary kinetic characterization suggests that tinostamustine and atpenin inhibit MPro by an irreversible and acompetitive mechanisms, respectively. Both drugs failed to inhibit the proliferation of SARS-CoV-2 in VERO cells. The virtual screening method reported here may be a powerful tool to further extent the identification of novel MPro inhibitors. Furthermore, the confirmed MPro hits may be subjected to optimization or retrospective search strategies to improve their molecular target and anti-viral potency.
Fil: Prada Gori, Denis Nihuel. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Ruatta Merke, Santiago Matías. Laboratorio de Biologia Redox de Tripanosomas ; Instituto Pasteur de Montevideo;
Fil: Fló, Martín. Universidad de la Republica. Facultad de Medicina; Uruguay
Fil: Alberca, Lucas Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina
Fil: Bellera, Carolina Leticia. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Park, Soonju. No especifíca;
Fil: Heo, Jinyeong. No especifíca;
Fil: Lee, Honggun. No especifíca;
Fil: Park, Kyu Ho Paul. No especifíca;
Fil: Otto Pritsch. Universidad de la Republica. Facultad de Medicina; Uruguay
Fil: Shum, David. No especifíca;
Fil: Comini, Marcelo A.. Laboratorio de Biologia Redox de Tripanosomas ; Instituto Pasteur de Montevideo;
Fil: Talevi, Alan. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Materia
ATPENIN
TINOSTAMUTINE
IN SILICO SCREENING
CYSTEINE PROTEASES
COVID-19
DRUG REPOSITIONING
SARS-COV-2
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:11336/219320
Acceder
id CONICETDig_19635b4abdf3153ac4799007fdcd8378
oai_identifier_str oai:ri.conicet.gov.ar:11336/219320
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Drug repurposing screening validated by experimental assays identifies two clinical drugs targeting SARS-CoV-2 main proteasePrada Gori, Denis NihuelRuatta Merke, Santiago MatíasFló, MartínAlberca, Lucas NicolásBellera, Carolina LeticiaPark, SoonjuHeo, JinyeongLee, HonggunPark, Kyu Ho PaulOtto PritschShum, DavidComini, Marcelo A.Talevi, AlanATPENINTINOSTAMUTINEIN SILICO SCREENINGCYSTEINE PROTEASESCOVID-19DRUG REPOSITIONINGSARS-COV-2https://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1The COVID-19 pandemic prompted several drug repositioning initiatives with the aim to rapidly deliver pharmacological candidates able to reduce SARS-CoV-2 dissemination and mortality. A major issue shared by many of the in silico studies addressing the discovery of compounds or drugs targeting SARS-CoV-2 molecules is that they lacked experimental validation of the results. Here we present a computer-aided drug-repositioning campaign against the indispensable SARS-CoV-2 main protease (MPro or 3CLPro) that involved the development of ligand-based ensemble models and the experimental testing of a small subset of the identified hits. The search method explored random subspaces of molecular descriptors to obtain linear classifiers. The best models were then combined by selective ensemble learning to improve their predictive power. Both the individual models and the ensembles were validated by retrospective screening, and later used to screen the DrugBank, Drug Repurposing Hub and Sweetlead libraries for potential inhibitors of MPro. From the 4 in silico hits assayed, atpenin and tinostamustine inhibited MPro (IC50 1 µM and 4 μM, respectively) but not the papain-like protease of SARS-CoV-2 (drugs tested at 25 μM). Preliminary kinetic characterization suggests that tinostamustine and atpenin inhibit MPro by an irreversible and acompetitive mechanisms, respectively. Both drugs failed to inhibit the proliferation of SARS-CoV-2 in VERO cells. The virtual screening method reported here may be a powerful tool to further extent the identification of novel MPro inhibitors. Furthermore, the confirmed MPro hits may be subjected to optimization or retrospective search strategies to improve their molecular target and anti-viral potency.Fil: Prada Gori, Denis Nihuel. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Ruatta Merke, Santiago Matías. Laboratorio de Biologia Redox de Tripanosomas ; Instituto Pasteur de Montevideo;Fil: Fló, Martín. Universidad de la Republica. Facultad de Medicina; UruguayFil: Alberca, Lucas Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; ArgentinaFil: Bellera, Carolina Leticia. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Park, Soonju. No especifíca;Fil: Heo, Jinyeong. No especifíca;Fil: Lee, Honggun. No especifíca;Fil: Park, Kyu Ho Paul. No especifíca;Fil: Otto Pritsch. Universidad de la Republica. Facultad de Medicina; UruguayFil: Shum, David. No especifíca;Fil: Comini, Marcelo A.. Laboratorio de Biologia Redox de Tripanosomas ; Instituto Pasteur de Montevideo;Fil: Talevi, Alan. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFrontiers Media2023-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/219320Prada Gori, Denis Nihuel; Ruatta Merke, Santiago Matías; Fló, Martín; Alberca, Lucas Nicolás; Bellera, Carolina Leticia; et al.; Drug repurposing screening validated by experimental assays identifies two clinical drugs targeting SARS-CoV-2 main protease; Frontiers Media; Frontiers in Drug Discovery; 2; 1-2023; 1-132674-0338CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.frontiersin.org/articles/10.3389/fddsv.2022.1082065/fullinfo:eu-repo/semantics/altIdentifier/doi/10.3389/fddsv.2022.1082065info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T11:00:35Zoai:ri.conicet.gov.ar:11336/219320instacron: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:34982025-10-22 11:00:35.612CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Drug repurposing screening validated by experimental assays identifies two clinical drugs targeting SARS-CoV-2 main protease
title Drug repurposing screening validated by experimental assays identifies two clinical drugs targeting SARS-CoV-2 main protease
spellingShingle Drug repurposing screening validated by experimental assays identifies two clinical drugs targeting SARS-CoV-2 main protease
Prada Gori, Denis Nihuel
ATPENIN
TINOSTAMUTINE
IN SILICO SCREENING
CYSTEINE PROTEASES
COVID-19
DRUG REPOSITIONING
SARS-COV-2
title_short Drug repurposing screening validated by experimental assays identifies two clinical drugs targeting SARS-CoV-2 main protease
title_full Drug repurposing screening validated by experimental assays identifies two clinical drugs targeting SARS-CoV-2 main protease
title_fullStr Drug repurposing screening validated by experimental assays identifies two clinical drugs targeting SARS-CoV-2 main protease
title_full_unstemmed Drug repurposing screening validated by experimental assays identifies two clinical drugs targeting SARS-CoV-2 main protease
title_sort Drug repurposing screening validated by experimental assays identifies two clinical drugs targeting SARS-CoV-2 main protease
dc.creator.none.fl_str_mv Prada Gori, Denis Nihuel
Ruatta Merke, Santiago Matías
Fló, Martín
Alberca, Lucas Nicolás
Bellera, Carolina Leticia
Park, Soonju
Heo, Jinyeong
Lee, Honggun
Park, Kyu Ho Paul
Otto Pritsch
Shum, David
Comini, Marcelo A.
Talevi, Alan
author Prada Gori, Denis Nihuel
author_facet Prada Gori, Denis Nihuel
Ruatta Merke, Santiago Matías
Fló, Martín
Alberca, Lucas Nicolás
Bellera, Carolina Leticia
Park, Soonju
Heo, Jinyeong
Lee, Honggun
Park, Kyu Ho Paul
Otto Pritsch
Shum, David
Comini, Marcelo A.
Talevi, Alan
author_role author
author2 Ruatta Merke, Santiago Matías
Fló, Martín
Alberca, Lucas Nicolás
Bellera, Carolina Leticia
Park, Soonju
Heo, Jinyeong
Lee, Honggun
Park, Kyu Ho Paul
Otto Pritsch
Shum, David
Comini, Marcelo A.
Talevi, Alan
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv ATPENIN
TINOSTAMUTINE
IN SILICO SCREENING
CYSTEINE PROTEASES
COVID-19
DRUG REPOSITIONING
SARS-COV-2
topic ATPENIN
TINOSTAMUTINE
IN SILICO SCREENING
CYSTEINE PROTEASES
COVID-19
DRUG REPOSITIONING
SARS-COV-2
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv The COVID-19 pandemic prompted several drug repositioning initiatives with the aim to rapidly deliver pharmacological candidates able to reduce SARS-CoV-2 dissemination and mortality. A major issue shared by many of the in silico studies addressing the discovery of compounds or drugs targeting SARS-CoV-2 molecules is that they lacked experimental validation of the results. Here we present a computer-aided drug-repositioning campaign against the indispensable SARS-CoV-2 main protease (MPro or 3CLPro) that involved the development of ligand-based ensemble models and the experimental testing of a small subset of the identified hits. The search method explored random subspaces of molecular descriptors to obtain linear classifiers. The best models were then combined by selective ensemble learning to improve their predictive power. Both the individual models and the ensembles were validated by retrospective screening, and later used to screen the DrugBank, Drug Repurposing Hub and Sweetlead libraries for potential inhibitors of MPro. From the 4 in silico hits assayed, atpenin and tinostamustine inhibited MPro (IC50 1 µM and 4 μM, respectively) but not the papain-like protease of SARS-CoV-2 (drugs tested at 25 μM). Preliminary kinetic characterization suggests that tinostamustine and atpenin inhibit MPro by an irreversible and acompetitive mechanisms, respectively. Both drugs failed to inhibit the proliferation of SARS-CoV-2 in VERO cells. The virtual screening method reported here may be a powerful tool to further extent the identification of novel MPro inhibitors. Furthermore, the confirmed MPro hits may be subjected to optimization or retrospective search strategies to improve their molecular target and anti-viral potency.
Fil: Prada Gori, Denis Nihuel. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Ruatta Merke, Santiago Matías. Laboratorio de Biologia Redox de Tripanosomas ; Instituto Pasteur de Montevideo;
Fil: Fló, Martín. Universidad de la Republica. Facultad de Medicina; Uruguay
Fil: Alberca, Lucas Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina
Fil: Bellera, Carolina Leticia. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Park, Soonju. No especifíca;
Fil: Heo, Jinyeong. No especifíca;
Fil: Lee, Honggun. No especifíca;
Fil: Park, Kyu Ho Paul. No especifíca;
Fil: Otto Pritsch. Universidad de la Republica. Facultad de Medicina; Uruguay
Fil: Shum, David. No especifíca;
Fil: Comini, Marcelo A.. Laboratorio de Biologia Redox de Tripanosomas ; Instituto Pasteur de Montevideo;
Fil: Talevi, Alan. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
description The COVID-19 pandemic prompted several drug repositioning initiatives with the aim to rapidly deliver pharmacological candidates able to reduce SARS-CoV-2 dissemination and mortality. A major issue shared by many of the in silico studies addressing the discovery of compounds or drugs targeting SARS-CoV-2 molecules is that they lacked experimental validation of the results. Here we present a computer-aided drug-repositioning campaign against the indispensable SARS-CoV-2 main protease (MPro or 3CLPro) that involved the development of ligand-based ensemble models and the experimental testing of a small subset of the identified hits. The search method explored random subspaces of molecular descriptors to obtain linear classifiers. The best models were then combined by selective ensemble learning to improve their predictive power. Both the individual models and the ensembles were validated by retrospective screening, and later used to screen the DrugBank, Drug Repurposing Hub and Sweetlead libraries for potential inhibitors of MPro. From the 4 in silico hits assayed, atpenin and tinostamustine inhibited MPro (IC50 1 µM and 4 μM, respectively) but not the papain-like protease of SARS-CoV-2 (drugs tested at 25 μM). Preliminary kinetic characterization suggests that tinostamustine and atpenin inhibit MPro by an irreversible and acompetitive mechanisms, respectively. Both drugs failed to inhibit the proliferation of SARS-CoV-2 in VERO cells. The virtual screening method reported here may be a powerful tool to further extent the identification of novel MPro inhibitors. Furthermore, the confirmed MPro hits may be subjected to optimization or retrospective search strategies to improve their molecular target and anti-viral potency.
publishDate 2023
dc.date.none.fl_str_mv 2023-01
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/11336/219320
Prada Gori, Denis Nihuel; Ruatta Merke, Santiago Matías; Fló, Martín; Alberca, Lucas Nicolás; Bellera, Carolina Leticia; et al.; Drug repurposing screening validated by experimental assays identifies two clinical drugs targeting SARS-CoV-2 main protease; Frontiers Media; Frontiers in Drug Discovery; 2; 1-2023; 1-13
2674-0338
CONICET Digital
CONICET
url http://hdl.handle.net/11336/219320
identifier_str_mv Prada Gori, Denis Nihuel; Ruatta Merke, Santiago Matías; Fló, Martín; Alberca, Lucas Nicolás; Bellera, Carolina Leticia; et al.; Drug repurposing screening validated by experimental assays identifies two clinical drugs targeting SARS-CoV-2 main protease; Frontiers Media; Frontiers in Drug Discovery; 2; 1-2023; 1-13
2674-0338
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.frontiersin.org/articles/10.3389/fddsv.2022.1082065/full
info:eu-repo/semantics/altIdentifier/doi/10.3389/fddsv.2022.1082065
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
application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Frontiers Media
publisher.none.fl_str_mv Frontiers Media
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
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score 12.982451

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