Abstract

Background: Severe acute respiratory syndrome coronavirus 2 main protease (SARSCoV- 2 M^pro) has been shown to be an effective target for inhibiting novel coronaviruses, which can be used as a crucial breakthrough for developing drugs to treat the coronavirus disease 2019 (COVID-19).

Methods: To design novel SARS-CoV-2 M^pro inhibitors, we conducted 3D-QSAR, molecular docking, and molecular dynamics (MD) simulation on 64 quinazolin-4-one derivatives.

Results: Comparative molecular field analysis (CoMFA) model (q² = 0.590, R2 = 0.962), comparative molecular similarity index analysis (CoMSIA) model (q² = 0.628, R² = 0.923), and external validation indicated that the stability, reliability, and prediction performance of our constructed model were excellent. We designed 8 inhibitors with stronger antiviral activities through the three-dimensional equipotential field. Molecular docking and MD simulation probed the interactions of compounds and SARS-CoV- 2 M^pro. This indicated that amino acid residues, including Met165, Met49, and Cys145, were very important in combination with the compounds. The prediction results of ADME/T and Lipinski’s rule of five indicated that the new compounds had favorable drug-like and pharmacokinetic properties.

Conclusion: This study provided new ideas for exploring novel SARS-CoV-2 M^pro inhibitors against COVID-19 in the future.

Keywords: SARS-CoV-2 M^pro inhibitors, Quinazolin-4-one derivatives, 3D-QSAR, molecular docking, molecular dynamics simulation, ADME/T.