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

dc.creatorPrada Gori, Denis Nihuel
dc.creatorRuatta, Santiago
dc.creatorFló, Martín
dc.creatorAlberca, Lucas Nicolás
dc.creatorBellera, Carolina Leticia
dc.creatorPark, Soonju
dc.creatorHeo, Jinyeong
dc.creatorLee, Honggun
dc.creatorPaul Park, Kyu-Ho
dc.creatorPritsch, Otto
dc.creatorShum, David
dc.creatorComini, Marcelo A.
dc.creatorTalevi, Alan
dc.date2023
dc.date2023-04-27T17:37:53Z
dc.identifierhttp://sedici.unlp.edu.ar/handle/10915/152249
dc.descriptionThe 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.
dc.descriptionLaboratorio de Investigación y Desarrollo de Bioactivos
dc.formatapplication/pdf
dc.languageen
dc.rightshttp://creativecommons.org/licenses/by/4.0/
dc.rightsCreative Commons Attribution 4.0 International (CC BY 4.0)
dc.subjectBiología
dc.subjectAtpenin
dc.subjectTinostamustine
dc.subjectIn silico screening
dc.subjectCysteine proteases
dc.subjectCOVID-19
dc.subjectDrug repositioning
dc.subjectSARS-CoV-2
dc.titleDrug repurposing screening validated by experimental assays identifies two clinical drugs targeting SARS-CoV-2 main protease
dc.typeArticulo
dc.typeArticulo


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