Ceftaroline fosamil for COVID-19

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In Silico and In Vitro Studies of the Approved Antibiotic Ceftaroline Fosamil and Its Metabolites as Inhibitors of SARS-CoV-2 Replication, Viruses, doi:10.3390/v17040491
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The SARS-CoV-2 proteases Mpro and PLpro are critical targets for antiviral drug development for the treatment of COVID-19. The 1,2,4-thiadiazole functional group is an inhibitor of cysteine proteases, such as papain and cathepsins. This chemical moiety is also present in ceftaroline fosamil (CF), an FDA-approved fifth-generation cephalosporin antibiotic. This study investigates the interactions between CF, its primary metabolites (M1 is dephosphorylated CF and M2 is an opened β-lactam ring) and derivatives (protonated M1H and M2H), and its open 1,2,4-thiadiazole rings derivatives (open-M1H and open-M2H) with SARS-CoV-2 proteases and evaluates CF’s effects on in vitro viral replication. In silico analyses (molecular docking and molecular dynamics (MD) simulations) demonstrated that CF and its metabolites are potential inhibitors of PLpro and Mpro. Docking analysis indicated that the majority of the ligands were more stable with Mpro than PLpro; however, in vitro biochemical analysis indicated PLpro as the preferred target for CF. CF inhibited viral replication in the human Calu-3 cell model at submicromolar concentrations when added to cell culture medium at 12 h. Our results suggest that CF should be evaluated as a potential repurposing agent for COVID-19, considering not only viral proteases but also other viral targets and relevant cellular pathways. Additionally, the reactivity of sulfur in the 1,2,4-thiadiazole moiety warrants further exploration for the development of viral protease inhibitors.
Virtual Screening and Quantum Chemistry Analysis for SARS-CoV-2 RNA-Dependent RNA Polymerase Using the ChEMBL Database: Reproduction of the Remdesivir-RTP and Favipiravir-RTP Binding Modes Obtained from Cryo-EM Experiments with High Binding Affinity, International Journal of Molecular Sciences, doi:10.3390/ijms231911009
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The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified as the pathogenic cause of coronavirus disease 2019 (COVID-19). The RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 is a potential target for the treatment of COVID-19. An RdRp complex:dsRNA structure suitable for docking simulations was prepared using a cryo-electron microscopy (cryo-EM) structure (PDB ID: 7AAP; resolution, 2.60 Å) that was reported recently. Structural refinement was performed using energy calculations. Structure-based virtual screening was performed using the ChEMBL database. Through 1,838,257 screenings, 249 drugs (37 approved, 93 clinical, and 119 preclinical drugs) were predicted to exhibit a high binding affinity for the RdRp complex:dsRNA. Nine nucleoside triphosphate analogs with anti-viral activity were included among these hit drugs, and among them, remdesivir-ribonucleoside triphosphate and favipiravir-ribonucleoside triphosphate adopted a similar docking mode as that observed in the cryo-EM structure. Additional docking simulations for the predicted compounds with high binding affinity for the RdRp complex:dsRNA suggested that 184 bioactive compounds could be anti-SARS-CoV-2 drug candidates. The hit bioactive compounds mainly consisted of a typical noncovalent major groove binder for dsRNA. Three-layer ONIOM (MP2/6-31G:AM1:AMBER) geometry optimization calculations and frequency analyses (MP2/6-31G:AMBER) were performed to estimate the binding free energy of a representative bioactive compound obtained from the docking simulation, and the fragment molecular orbital calculation at the MP2/6-31G level of theory was subsequently performed for analyzing the detailed interactions. The procedure used in this study represents a possible strategy for discovering anti-SARS-CoV-2 drugs from drug libraries that could significantly shorten the clinical development period for drug repositioning.
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