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: Coronaviruses; SARS-CoV-2; Medicinal & Biomolecular Chemistry; 610; COVID-19; Coronavirus Papain-Like Proteases; Computation Theory and Mathematics; Antiviral Agents; 3. Good health; Molecular Docking Simulation; Medicinal and Biomolecular Chemistry; Infectious Diseases; Emerging Infectious Diseases; Theoretical and Computational Chemistry; Theoretical and computational chemistry; Chemical Sciences; Papain; Medicinal and biomolecular chemistry; Humans; Protease Inhibitors; Infection; Coronavirus 3C Proteases; Naphthoquinones

AbstractThe 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 the present work, 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 66 µM. In addition, eight compounds inhibited PLpro with IC50 ranging from 1.7 µM to 46 µM. 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.