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 (LD5 n ≈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; M₆ 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.

Keywords

SARS-CoV-2 / Docking / DFT / CNS-safe flavone / Molecular dynamics

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

CRediT authorship contribution statement

Oussama Khibech: Writing – review & editing, Writing – original draft, Software, Methodology, Conceptualization. Mohammed Ouachekradi: Writing – review & editing, Writing – original draft, Visualization, Software, Methodology, Investigation. Mohammed Merzouki: Validation, Investigation, Formal analysis, Conceptualization. Abdessamad Benabbou: Validation, Investigation, Formal analysis, Conceptualization. Said Abadi: Writing – review & editing, Visualization, Software, Resources, Investigation. Yasser Karzazi: Writing – review & editing, Validation, Supervision, Methodology. Boufelja Bouammalli: Writing – review & editing, Visualization, Validation, Supervision, Methodology. Allal Challioui: Writing – review & editing, Writing – original draft, Validation, Supervision, Software, Resources, Methodology.

Acknowledgements

We gratefully acknowledge the Marwan HPC team for granting us privileged access to their high-performance computing resources. The exceptional computational power and prompt technical assistance they provided were essential for the molecular-dynamics simulations presented here, substantially strengthening the scope and robustness of our results.

Supplementary materials

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.chphma.2025.10.007.

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