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

Autores
Prada Gori, Denis Nihuel; Ruatta, Santiago; Fló, Martín; Alberca, Lucas Nicolás; Bellera, Carolina Leticia; Park, Soonju; Heo, Jinyeong; Lee, Honggun; Paul Park, Kyu-Ho; Pritsch, Otto; 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 SARSCoV- 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 SARSCoV- 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 SARSCoV- 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.
Laboratorio de Investigación y Desarrollo de Bioactivos
Materia
Biología
Atpenin
Tinostamustine
In silico screening
Cysteine proteases
COVID-19
Drug repositioning
SARS-CoV-2
Nivel de accesibilidad
acceso abierto
Condiciones de uso
http://creativecommons.org/licenses/by/4.0/
Repositorio
SEDICI (UNLP)
Institución
Universidad Nacional de La Plata
OAI Identificador
oai:sedici.unlp.edu.ar:10915/152249

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network_name_str SEDICI (UNLP)
spelling Drug repurposing screening validated by experimental assays identifies two clinical drugs targeting SARS-CoV-2 main proteasePrada Gori, Denis NihuelRuatta, SantiagoFló, MartínAlberca, Lucas NicolásBellera, Carolina LeticiaPark, SoonjuHeo, JinyeongLee, HonggunPaul Park, Kyu-HoPritsch, OttoShum, DavidComini, Marcelo A.Talevi, AlanBiologíaAtpeninTinostamustineIn silico screeningCysteine proteasesCOVID-19Drug repositioningSARS-CoV-2The COVID-19 pandemic prompted several drug repositioning initiatives with the aim to rapidly deliver pharmacological candidates able to reduce SARSCoV- 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 SARSCoV- 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 SARSCoV- 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.Laboratorio de Investigación y Desarrollo de Bioactivos2023info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionArticulohttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfhttp://sedici.unlp.edu.ar/handle/10915/152249enginfo:eu-repo/semantics/altIdentifier/issn/2674-0338info:eu-repo/semantics/altIdentifier/doi/10.3389/fddsv.2022.1082065info:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by/4.0/Creative Commons Attribution 4.0 International (CC BY 4.0)reponame:SEDICI (UNLP)instname:Universidad Nacional de La Platainstacron:UNLP2025-09-29T11:39:17Zoai:sedici.unlp.edu.ar:10915/152249Institucionalhttp://sedici.unlp.edu.ar/Universidad públicaNo correspondehttp://sedici.unlp.edu.ar/oai/snrdalira@sedici.unlp.edu.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:13292025-09-29 11:39:17.493SEDICI (UNLP) - Universidad Nacional de La Platafalse
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
Biología
Atpenin
Tinostamustine
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, Santiago
Fló, Martín
Alberca, Lucas Nicolás
Bellera, Carolina Leticia
Park, Soonju
Heo, Jinyeong
Lee, Honggun
Paul Park, Kyu-Ho
Pritsch, Otto
Shum, David
Comini, Marcelo A.
Talevi, Alan
author Prada Gori, Denis Nihuel
author_facet Prada Gori, Denis Nihuel
Ruatta, Santiago
Fló, Martín
Alberca, Lucas Nicolás
Bellera, Carolina Leticia
Park, Soonju
Heo, Jinyeong
Lee, Honggun
Paul Park, Kyu-Ho
Pritsch, Otto
Shum, David
Comini, Marcelo A.
Talevi, Alan
author_role author
author2 Ruatta, Santiago
Fló, Martín
Alberca, Lucas Nicolás
Bellera, Carolina Leticia
Park, Soonju
Heo, Jinyeong
Lee, Honggun
Paul Park, Kyu-Ho
Pritsch, Otto
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 Biología
Atpenin
Tinostamustine
In silico screening
Cysteine proteases
COVID-19
Drug repositioning
SARS-CoV-2
topic Biología
Atpenin
Tinostamustine
In silico screening
Cysteine proteases
COVID-19
Drug repositioning
SARS-CoV-2
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 SARSCoV- 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 SARSCoV- 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 SARSCoV- 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.
Laboratorio de Investigación y Desarrollo de Bioactivos
description The COVID-19 pandemic prompted several drug repositioning initiatives with the aim to rapidly deliver pharmacological candidates able to reduce SARSCoV- 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 SARSCoV- 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 SARSCoV- 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
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
Articulo
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dc.identifier.none.fl_str_mv http://sedici.unlp.edu.ar/handle/10915/152249
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dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/issn/2674-0338
info:eu-repo/semantics/altIdentifier/doi/10.3389/fddsv.2022.1082065
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
http://creativecommons.org/licenses/by/4.0/
Creative Commons Attribution 4.0 International (CC BY 4.0)
eu_rights_str_mv openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by/4.0/
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