Inhibition Potential of Quercetin Similar Compounds to SARS-CoV-2 Main Protease by High-Throughput Virtual Screening, Molecular Simulations, ADMET Analysis, and DFT Studies.

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.