Structure-Based Identification of Naphthoquinones and Derivatives as Novel Inhibitors of Main Protease Mpro and Papain-like Protease PLpro of SARS-CoV-2

• DOI: 10.1021/acs.jcim.2c00693
• Publication Date: 2022-08-12T17:03:06Z
• Authors: Lucianna H. Santos; Thales Kronenberger; Renata G. Almeida; Elany B. Silva; Rafael E. O. Rocha; Joyce C. Oliveira; Luiza V. Barreto; Danielle Skinner; Pavla Fajtová; Miriam A. Giardini; Brendon Woodworth; Conner Bardine; André L. Lourenço; Charles S. Craik; Antti Poso; Larissa M. Podust; James H. McKerrow; Jair L. Siqueira-...; Anthony J. O’Dono...; Eufrânio N. da Si...; Rafaela S. Ferreira
• Keywords: Polyproteins; IC50

The worldwide COVID-19 pandemic caused by the coronavirus SARS-CoV-2 urgently demands novel direct antiviral treatments. main protease (Mpro) and papain-like (PLpro) are attractive drug targets among coronaviruses due to their essential role in processing polyproteins translated from viral RNA. In this study, we virtually screened 688 naphthoquinoidal compounds derivatives against Mpro of SARS-CoV-2. Twenty-four were selected evaluated biochemical assays using a fluorogenic substrate. parallel, these also assayed with PLpro. Four inhibited half-maximal inhibitory concentration (IC50) values between 0.41 μM 9.0 μM. addition, three PLpro IC50 ranging 1.9 3.3 To verify specificity inhibitors, our experiments included an assessment common causes false positives such as aggregation, high compound fluorescence, inhibition enzyme oxidation. Altogether, confirmed classes specific inhibitors. Molecular dynamics simulations suggest stable binding modes for inhibitors frequent interactions residues S1 S2 pockets active site. For two occur S3 S4 pockets. summary, structure-based computational approach identified naphthoquinonal scaffolds that can be further explored antivirals.