Inhibition Potential of Quercetin Similar Compounds to SARS-CoV-2 Main Protease by High-Throughput Virtual Screening,...

This study focused on in silico investigation of SARS-CoV-2 Mpro inhibitors screened from 6663 quercetin similar compounds. Two promising compounds, blumeatin B (L₁) and 3,5-dihydroxy-7,3',4',5'-tetramethoxyflavone (L₂), were identified through machine learning based virtual screening and similarity analysis. They underwent molecular docking with Mpro and demonstrated strong interactions, with docking scores of -8.02 and -7.21 kcal/mol, respectively. Various parameters (RMSD, RMSF, Rg, SASA, and the number of hydrogen bonds) observed during 200 ns molecular dynamics (MD) simulation confirmed their stability. Principal component analysis (PCA) and dynamical cross-correlation matrix (DCCM) revealed minimal conformational changes and strongly correlated motions in the protein. End-state MM/GBSA free energy calculations for L₁ and L₂ with Mpro were -22.86 and -19.89 kcal/mol. Density functional theory (DFT) studies at the B3LYP/6-311++G (d,p) level showed their polar nature, with electrophilicity index values exceeding 1.5 eV. The HOMO-LUMO energy gaps of L₁ and L₂ were 4.04 and 3.57 eV, aligning with the DOS spectra. Based on results from virtual screening, ADMET parameters, docking scores, hydrophobic interactions, hydrogen bonding, MD simulation, end-state free energy calculations, and DFT findings, L₁ and L₂ could be considered as promising SARS-CoV-2 Mpro inhibitors, requiring further experimental validation.