CNS-safe flavone analogues as dual SARS-CoV-2 inhibitors: An integrated in-silico design study

Abstract

Because SARS-CoV-2 infection can provoke neurological complications, prospective antivirals must combine high viral potency with central-nervous-system (CNS) safety. Seven flavone-derived analogues (M1–M7) were therefore evaluated with a fully in-silico workflow that linked ADME filtering, ProTox-III neuro-toxicity prediction, multi-target docking (main protease M pro: 7RN1, 9ARQ, 9ART; ACE2: 7UFL), density functional theory (DFT) and 100 ns atomistic molecular-dynamics (MD) simulations. SwissADME and ADMETlab 3 indicated full compliance with Lipinski, Veber and Ghose rules, balanced polarity-lipophilicity and predicted human intestinal absorption of 2%–28%, while all analogues remained outside blood-brain-barrier risk space. ProTox-III placed the series in GHS hazard class 5 (LD₅₀ ≈ 2500–4000 mg kg −1 ) with ≥ 84% probability of neuro-inactivity. Docking returned mean binding energies of −7.0 kcal mol −1 for M pro and −7.5 kcal mol −1 for ACE2; M 6 ranked first for M pro through hydrogen bonds to CYS145 and GLN189, whereas M4 and M7 favoured ACE2 via a GLN98/TYR196 network. Redocking reproduced co-crystal poses with RMSD ≤ 1.52 Å, validating the protocol. MD confirmed stability: M6-M pro and M4-ACE2 plateaued at ligand RMSD ≤ 0.6 nm and damped catalytic-site RMSF, whereas M7-ACE2 drifted after 70 ns. DFT revealed that M6 possesses the narrowest HOMO-LUMO gap (3.47 eV) and highest electrophilicity ( ω = 7.17 eV), rationalising its reactivity. Convergent evidence identifies M6, M4 and M7 as CNS-safe, drug-like antivirals worthy of experimental validation.