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Structure-Based Identification of Naphthoquinones and Derivatives as Novel Inhibitors of Main Protease Mpro and Papain-like Protease PLpro of SARS-CoV-2
LH. Santos, T. Kronenberger, RG. Almeida, EB. Silva, REO. Rocha, JC. Oliveira, LV. Barreto, D. Skinner, P. Fajtová, MA. Giardini, B. Woodworth, C. Bardine, AL. Lourenço, CS. Craik, A. Poso, LM. Podust, JH. McKerrow, JL. Siqueira-Neto, AJ....
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články, práce podpořená grantem, Research Support, N.I.H., Extramural
Grantová podpora
P50 AI150476
NIAID NIH HHS - United States
T32 GM145460
NIGMS NIH HHS - United States
U19 AI171110
NIAID NIH HHS - United States
PubMed
35960688
DOI
10.1021/acs.jcim.2c00693
Knihovny.cz E-zdroje
- MeSH
- antivirové látky * farmakologie chemie MeSH
- COVID-19 MeSH
- inhibitory proteas * farmakologie chemie MeSH
- koronavirové proteasy 3C * antagonisté a inhibitory MeSH
- koronavirové proteasy podobné papainu * antagonisté a inhibitory MeSH
- lidé MeSH
- naftochinony * chemie farmakologie MeSH
- papain MeSH
- SARS-CoV-2 * účinky léků enzymologie MeSH
- simulace molekulového dockingu MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
The worldwide COVID-19 pandemic caused by the coronavirus SARS-CoV-2 urgently demands novel direct antiviral treatments. The main protease (Mpro) and papain-like protease (PLpro) are attractive drug targets among coronaviruses due to their essential role in processing the polyproteins translated from the viral RNA. In this study, we virtually screened 688 naphthoquinoidal compounds and derivatives against Mpro of SARS-CoV-2. Twenty-four derivatives were selected and evaluated in biochemical assays against Mpro using a novel fluorogenic substrate. In parallel, these compounds were also assayed with SARS-CoV-2 PLpro. Four compounds inhibited Mpro with half-maximal inhibitory concentration (IC50) values between 0.41 μM and 9.0 μM. In addition, three compounds inhibited PLpro with IC50 ranging from 1.9 μM to 3.3 μM. To verify the specificity of Mpro and PLpro inhibitors, our experiments included an assessment of common causes of false positives such as aggregation, high compound fluorescence, and inhibition by enzyme oxidation. Altogether, we confirmed novel classes of specific Mpro and PLpro inhibitors. Molecular dynamics simulations suggest stable binding modes for Mpro inhibitors with frequent interactions with residues in the S1 and S2 pockets of the active site. For two PLpro inhibitors, interactions occur in the S3 and S4 pockets. In summary, our structure-based computational and biochemical approach identified novel naphthoquinonal scaffolds that can be further explored as SARS-CoV-2 antivirals.
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- $a Santos, Lucianna H $u Department of Biochemistry and Immunology, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil
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- $a Structure-Based Identification of Naphthoquinones and Derivatives as Novel Inhibitors of Main Protease Mpro and Papain-like Protease PLpro of SARS-CoV-2 / $c LH. Santos, T. Kronenberger, RG. Almeida, EB. Silva, REO. Rocha, JC. Oliveira, LV. Barreto, D. Skinner, P. Fajtová, MA. Giardini, B. Woodworth, C. Bardine, AL. Lourenço, CS. Craik, A. Poso, LM. Podust, JH. McKerrow, JL. Siqueira-Neto, AJ. O'Donoghue, EN. da Silva Júnior, RS. Ferreira
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- $a The worldwide COVID-19 pandemic caused by the coronavirus SARS-CoV-2 urgently demands novel direct antiviral treatments. The main protease (Mpro) and papain-like protease (PLpro) are attractive drug targets among coronaviruses due to their essential role in processing the polyproteins translated from the viral RNA. In this study, we virtually screened 688 naphthoquinoidal compounds and derivatives against Mpro of SARS-CoV-2. Twenty-four derivatives were selected and evaluated in biochemical assays against Mpro using a novel fluorogenic substrate. In parallel, these compounds were also assayed with SARS-CoV-2 PLpro. Four compounds inhibited Mpro with half-maximal inhibitory concentration (IC50) values between 0.41 μM and 9.0 μM. In addition, three compounds inhibited PLpro with IC50 ranging from 1.9 μM to 3.3 μM. To verify the specificity of Mpro and PLpro inhibitors, our experiments included an assessment of common causes of false positives such as aggregation, high compound fluorescence, and inhibition by enzyme oxidation. Altogether, we confirmed novel classes of specific Mpro and PLpro inhibitors. Molecular dynamics simulations suggest stable binding modes for Mpro inhibitors with frequent interactions with residues in the S1 and S2 pockets of the active site. For two PLpro inhibitors, interactions occur in the S3 and S4 pockets. In summary, our structure-based computational and biochemical approach identified novel naphthoquinonal scaffolds that can be further explored as SARS-CoV-2 antivirals.
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