Počet záznamů: 1
Structure-based identification of naphthoquinones and derivatives as novel inhibitors of main protease Mpro and papain-like protease PLpro of SARS-CoV-2
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SYSNO ASEP 0560992 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název Structure-based identification of naphthoquinones and derivatives as novel inhibitors of main protease Mpro and papain-like protease PLpro of SARS-CoV-2 Tvůrce(i) Santos, L. H. (BR)
Kronenberger, T. (DE)
Almeida, R. G. (BR)
Silva, E. B. (US)
Rocha, R. E. O. (BR)
Oliveira, J. C. (BR)
Barreto, L. V. (BR)
Skinner, D. (US)
Fajtová, Pavla (UOCHB-X) RID, ORCID
Giardini, M. A. (US)
Woodworth, B. (US)
Bardine, C. (US)
Lourenço, A. L. (US)
Craik, C. S. (US)
Poso, A. (FI)
Podust, L. M. (US)
McKerrow, J. H. (US)
Siqueira-Neto, J. L. (US)
O'Donoghue, A. J. (US)
Da Silva Júnior, E. N. (BR)
Ferreira, R. S. (BR)Zdroj.dok. Journal of Chemical Information and Modeling. - : American Chemical Society - ISSN 1549-9596
Roč. 62, č. 24 (2022), s. 6553-6573Poč.str. 21 s. Jazyk dok. eng - angličtina Země vyd. US - Spojené státy americké Klíč. slova nor-β-lapachone ; Trypanosoma cruzi activity ; potent antitumor activity Obor OECD Biochemistry and molecular biology Způsob publikování Omezený přístup Institucionální podpora UOCHB-X - RVO:61388963 UT WOS 000870157000001 EID SCOPUS 85136662485 DOI 10.1021/acs.jcim.2c00693 Anotace 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. Pracoviště Ústav organické chemie a biochemie Kontakt asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Jana Procházková, Tel.: 220 183 418 Rok sběru 2023 Elektronická adresa https://doi.org/10.1021/acs.jcim.2c00693
Počet záznamů: 1