Novel inhibitors of the main protease enzyme of SARS-CoV-2 identified via molecular dynamics simulation-guided in vitro assay

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MetadadosDescriçãoIdioma
Autor(es): dc.contributorInstitute of Biological Information Processing: Structural Biochemistry (IBI-7)-
Autor(es): dc.contributorHeinrich Heine University Düsseldorf-
Autor(es): dc.contributorUniversidade Estadual Paulista (Unesp)-
Autor(es): dc.contributorObafemi Awolowo University-
Autor(es): dc.creatorLoschwitz, Jennifer-
Autor(es): dc.creatorJäckering, Anna-
Autor(es): dc.creatorKeutmann, Monika-
Autor(es): dc.creatorOlagunju, Maryam-
Autor(es): dc.creatorEberle, Raphael J. [UNESP]-
Autor(es): dc.creatorCoronado, Monika Aparecida-
Autor(es): dc.creatorOlubiyi, Olujide O.-
Autor(es): dc.creatorStrodel, Birgit-
Data de aceite: dc.date.accessioned2022-02-22T00:46:21Z-
Data de disponibilização: dc.date.available2022-02-22T00:46:21Z-
Data de envio: dc.date.issued2021-06-25-
Data de envio: dc.date.issued2021-06-25-
Data de envio: dc.date.issued2021-06-01-
Fonte completa do material: dc.identifierhttp://dx.doi.org/10.1016/j.bioorg.2021.104862-
Fonte completa do material: dc.identifierhttp://hdl.handle.net/11449/206174-
Fonte: dc.identifier.urihttp://educapes.capes.gov.br/handle/11449/206174-
Descrição: dc.descriptionFor the COVID-19 pandemic caused by SARS-CoV-2, there are currently no effective drugs or vaccines to treat this coronavirus infection. In this study, we focus on the main protease enzyme of SARS-CoV-2, 3CLpro, which is critical for viral replication. We employ explicit solvent molecular dynamics simulations of about 150 compounds docked into 3CLpro’s binding site and that had emerged as good main protease ligands from our previous in silico screening of over 1.2 million compounds. By incoporating protein dynamics and applying a range of structural descriptors, such as the ability to form specific contacts with the catalytic dyad residues of 3CLpro and the structural fluctuations of the ligands in the binding site, we are able to further refine our compound selection. Fourteen compounds including estradiol shown to be the most promising based on our calculations were procured and screened against recombinant 3CLpro in a fluorescence assay. Eight of these compounds have significant activity in inhibiting the SARS-CoV-2 main protease. Among these are corilagin, a gallotannin, and lurasidone, an antipsychotic drug, which emerged as the most promising natural product and drug, respectively, and might thus be candidates for drug repurposing for the treatment of COVID-19. In addition, we also tested the inhibitory activity of testosterone, and our results reveal testosterone as possessing moderate inhibitory potency against the 3CLpro enzyme, which may thus provide an explanation why older men are more severely affected by COVID-19.-
Descrição: dc.descriptionInstitute of Biological Information Processing: Structural Biochemistry (IBI-7), Forschungszentrum Jülich-
Descrição: dc.descriptionInstitute of Theoretical and Computational Chemistry Heinrich Heine University Düsseldorf-
Descrição: dc.descriptionMultiuser Center for Biomolecular Innovation IBILCE Universidade Estadual Paulista (UNESP)-
Descrição: dc.descriptionDepartment of Pharmaceutical Chemistry Faculty of Pharmacy Obafemi Awolowo University-
Descrição: dc.descriptionMultiuser Center for Biomolecular Innovation IBILCE Universidade Estadual Paulista (UNESP)-
Idioma: dc.languageen-
Relação: dc.relationBioorganic Chemistry-
???dc.source???: dc.sourceScopus-
Palavras-chave: dc.subject3CLpro-
Palavras-chave: dc.subjectCOVID-19-
Palavras-chave: dc.subjectDrug repurposing-
Palavras-chave: dc.subjectEnzyme inhibition assay-
Palavras-chave: dc.subjectMD simulations-
Palavras-chave: dc.subjectNatural products-
Palavras-chave: dc.subjectViral replication inhibition-
Título: dc.titleNovel inhibitors of the main protease enzyme of SARS-CoV-2 identified via molecular dynamics simulation-guided in vitro assay-
Tipo de arquivo: dc.typelivro digital-
Aparece nas coleções:Repositório Institucional - Unesp

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