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dc.date.accessioned 2023-04-27T17:37:53Z
dc.date.available 2023-04-27T17:37:53Z
dc.date.issued 2023
dc.identifier.uri http://sedici.unlp.edu.ar/handle/10915/152249
dc.description.abstract 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. en
dc.language en es
dc.subject Atpenin es
dc.subject Tinostamustine es
dc.subject In silico screening es
dc.subject Cysteine proteases es
dc.subject COVID-19 es
dc.subject Drug repositioning es
dc.subject SARS-CoV-2 es
dc.title Drug repurposing screening validated by experimental assays identifies two clinical drugs targeting SARS-CoV-2 main protease en
dc.type Articulo es
sedici.identifier.other https://doi.org/10.3389/fddsv.2022.1082065 es
sedici.identifier.issn 2674-0338 es
sedici.creator.person Prada Gori, Denis Nihuel es
sedici.creator.person Ruatta, Santiago es
sedici.creator.person Fló, Martín es
sedici.creator.person Alberca, Lucas Nicolás es
sedici.creator.person Bellera, Carolina Leticia es
sedici.creator.person Park, Soonju es
sedici.creator.person Heo, Jinyeong es
sedici.creator.person Lee, Honggun es
sedici.creator.person Paul Park, Kyu-Ho es
sedici.creator.person Pritsch, Otto es
sedici.creator.person Shum, David es
sedici.creator.person Comini, Marcelo A. es
sedici.creator.person Talevi, Alan es
sedici.subject.materias Biología es
sedici.description.fulltext true es
mods.originInfo.place Laboratorio de Investigación y Desarrollo de Bioactivos es
sedici.subtype Articulo es
sedici.rights.license Creative Commons Attribution 4.0 International (CC BY 4.0)
sedici.rights.uri http://creativecommons.org/licenses/by/4.0/
sedici.description.peerReview peer-review es
sedici.relation.journalTitle Frontiers in Drug Discovery es
sedici.relation.journalVolumeAndIssue vol. 2 es

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Creative Commons Attribution 4.0 International (CC BY 4.0) Except where otherwise noted, this item's license is described as Creative Commons Attribution 4.0 International (CC BY 4.0)