Integrated Computational Study Prioritizes Drug-like Para-Flavonoids as Candidate SARS-CoV-2 Mpro Inhibitors

Emerging SARS-CoV-2 variants highlight the need for orally active, low-toxicity antivirals. We designed seven para-substituted flavonoid hybrids (M1–M7) against the main protease (Mpro). In silico ADME filtering revealed zero Lipinski, Veber, or Ghose violations, a SwissADME bioavailability score of 0.55, and selected favorable predicted absorption and transporter endpoints relative to lopinavir, without implying measured pharmacokinetic superiority. ProTox-III indicated that amino and nitro substitution increased predicted genotoxicity liabilities, whereas cyano and methoxy substitution reduced selected endocrine-related signals. AutoDock Vina docking to Mpro (PDB 9C8Q; redocking RMSD 0.316 Å) ranked the nitro analogue M6 first among the designed compounds (−8.1 kcal mol−1), with contacts involving His41 and neighboring active-site residues. During the 100 ns GROMACS simulations, the protein backbone remained stable, whereas M6 adopted a late reoriented pose that was retained in the active-site region and supported by late-window per-residue energetic contributions. DFT calculations at the B3LYP/6-311G(d,p) level identified the narrowest HOMO-LUMO gap (3.44 eV) and highest electrophilicity (ω = 6.2 eV) for M6. Overall, M6 is prioritized as a computational lead requiring Mpro inhibition, antiviral, and cytotoxicity validation.