Peer Review #3 of "Antiviral drug discovery by targeting the SARS-CoV-2 polyprotein processing by inhibition of the main protease (v0.1)"
Abstract
The spread of SARS CoV-2, the causative agent for COVID-19, has led to a global and deadly pandemic.To date, few drugs have been approved for treating SARS CoV-2 infections.In this study, a structure-based approach was adopted using the SARS CoV-2 main protease (M pro ) and a carefully selected dataset of 37060 compounds comprising M pro and antiviral protein-specific libraries.The compounds passed two-step docking filtration, starting with standard precision (SP) followed by extra precision (XP) runs.Fourteen compounds with the highest XP docking scores were examined by 20 ns molecular dynamics simulations (MDs).Based on backbone route mean square deviations (RMSD) and molecular mechanics/generalized Born surface area (MM/GBSA) binding energy, four drugs were selected for comprehensive MDs analysis at 100 ns.Results indicated that birinapant, atazanavir, and ritonavir potently bound and stabilized SARS CoV-2 M pro structure.Binding energies higher than -102 kcal/mol, RMSD values <0.22 nm, formation of several hydrogen bonds with M pro , favourable electrostatic contributions, and low radii of gyration were among the estimated factors contributing to the strength of the binding of these three compounds with M pro .The top two compounds, atazanavir and birinapant, were tested for their ability to prevent SARS-CoV-2 plaque formation.At 10 µM of birinapant concentration, antiviral tests against SARS-CoV-2 demonstrated a 37% reduction of virus multiplication.Antiviral assays…
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