Novel inhibitors of the main protease enzyme of SARS-CoV-2 identified via molecular dynamics simulation-guided in vitro assay
Autor(a) principal: | |
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Data de Publicação: | 2021 |
Outros Autores: | , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNESP |
Texto Completo: | http://dx.doi.org/10.1016/j.bioorg.2021.104862 http://hdl.handle.net/11449/206174 |
Resumo: | For 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. |
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Novel inhibitors of the main protease enzyme of SARS-CoV-2 identified via molecular dynamics simulation-guided in vitro assay3CLproCOVID-19Drug repurposingEnzyme inhibition assayMD simulationsNatural productsViral replication inhibitionFor 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.Institute of Biological Information Processing: Structural Biochemistry (IBI-7), Forschungszentrum JülichInstitute of Theoretical and Computational Chemistry Heinrich Heine University DüsseldorfMultiuser Center for Biomolecular Innovation IBILCE Universidade Estadual Paulista (UNESP)Department of Pharmaceutical Chemistry Faculty of Pharmacy Obafemi Awolowo UniversityMultiuser Center for Biomolecular Innovation IBILCE Universidade Estadual Paulista (UNESP)Institute of Biological Information Processing: Structural Biochemistry (IBI-7)Heinrich Heine University DüsseldorfUniversidade Estadual Paulista (Unesp)Obafemi Awolowo UniversityLoschwitz, JenniferJäckering, AnnaKeutmann, MonikaOlagunju, MaryamEberle, Raphael J. [UNESP]Coronado, Monika AparecidaOlubiyi, Olujide O.Strodel, Birgit2021-06-25T10:27:45Z2021-06-25T10:27:45Z2021-06-01info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://dx.doi.org/10.1016/j.bioorg.2021.104862Bioorganic Chemistry, v. 111.1090-21200045-2068http://hdl.handle.net/11449/20617410.1016/j.bioorg.2021.1048622-s2.0-85103951202Scopusreponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengBioorganic Chemistryinfo:eu-repo/semantics/openAccess2021-10-22T21:54:32Zoai:repositorio.unesp.br:11449/206174Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462024-08-05T21:14:15.555601Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false |
dc.title.none.fl_str_mv |
Novel inhibitors of the main protease enzyme of SARS-CoV-2 identified via molecular dynamics simulation-guided in vitro assay |
title |
Novel inhibitors of the main protease enzyme of SARS-CoV-2 identified via molecular dynamics simulation-guided in vitro assay |
spellingShingle |
Novel inhibitors of the main protease enzyme of SARS-CoV-2 identified via molecular dynamics simulation-guided in vitro assay Loschwitz, Jennifer 3CLpro COVID-19 Drug repurposing Enzyme inhibition assay MD simulations Natural products Viral replication inhibition |
title_short |
Novel inhibitors of the main protease enzyme of SARS-CoV-2 identified via molecular dynamics simulation-guided in vitro assay |
title_full |
Novel inhibitors of the main protease enzyme of SARS-CoV-2 identified via molecular dynamics simulation-guided in vitro assay |
title_fullStr |
Novel inhibitors of the main protease enzyme of SARS-CoV-2 identified via molecular dynamics simulation-guided in vitro assay |
title_full_unstemmed |
Novel inhibitors of the main protease enzyme of SARS-CoV-2 identified via molecular dynamics simulation-guided in vitro assay |
title_sort |
Novel inhibitors of the main protease enzyme of SARS-CoV-2 identified via molecular dynamics simulation-guided in vitro assay |
author |
Loschwitz, Jennifer |
author_facet |
Loschwitz, Jennifer Jäckering, Anna Keutmann, Monika Olagunju, Maryam Eberle, Raphael J. [UNESP] Coronado, Monika Aparecida Olubiyi, Olujide O. Strodel, Birgit |
author_role |
author |
author2 |
Jäckering, Anna Keutmann, Monika Olagunju, Maryam Eberle, Raphael J. [UNESP] Coronado, Monika Aparecida Olubiyi, Olujide O. Strodel, Birgit |
author2_role |
author author author author author author author |
dc.contributor.none.fl_str_mv |
Institute of Biological Information Processing: Structural Biochemistry (IBI-7) Heinrich Heine University Düsseldorf Universidade Estadual Paulista (Unesp) Obafemi Awolowo University |
dc.contributor.author.fl_str_mv |
Loschwitz, Jennifer Jäckering, Anna Keutmann, Monika Olagunju, Maryam Eberle, Raphael J. [UNESP] Coronado, Monika Aparecida Olubiyi, Olujide O. Strodel, Birgit |
dc.subject.por.fl_str_mv |
3CLpro COVID-19 Drug repurposing Enzyme inhibition assay MD simulations Natural products Viral replication inhibition |
topic |
3CLpro COVID-19 Drug repurposing Enzyme inhibition assay MD simulations Natural products Viral replication inhibition |
description |
For 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. |
publishDate |
2021 |
dc.date.none.fl_str_mv |
2021-06-25T10:27:45Z 2021-06-25T10:27:45Z 2021-06-01 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://dx.doi.org/10.1016/j.bioorg.2021.104862 Bioorganic Chemistry, v. 111. 1090-2120 0045-2068 http://hdl.handle.net/11449/206174 10.1016/j.bioorg.2021.104862 2-s2.0-85103951202 |
url |
http://dx.doi.org/10.1016/j.bioorg.2021.104862 http://hdl.handle.net/11449/206174 |
identifier_str_mv |
Bioorganic Chemistry, v. 111. 1090-2120 0045-2068 10.1016/j.bioorg.2021.104862 2-s2.0-85103951202 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Bioorganic Chemistry |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.source.none.fl_str_mv |
Scopus reponame:Repositório Institucional da UNESP instname:Universidade Estadual Paulista (UNESP) instacron:UNESP |
instname_str |
Universidade Estadual Paulista (UNESP) |
instacron_str |
UNESP |
institution |
UNESP |
reponame_str |
Repositório Institucional da UNESP |
collection |
Repositório Institucional da UNESP |
repository.name.fl_str_mv |
Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP) |
repository.mail.fl_str_mv |
|
_version_ |
1808129300302397440 |