Computational evaluation of chromone-tetrazole hybrids as noncovalent inhibitors of SARS-CoV-2 Mpro.

Abstract

Emerging SARS-CoV-2 variants continue to demand orally tractable, non-covalent inhibitors of the conserved main protease (Mpro). Here, chromone-phenyl-tetrazole hybrids were prioritized using a multiscale computational strategy that connects drug-likeness, binding stability, free-energy ranking, conformational behavior, and quantum-level electronic features. The series showed favorable oral drug-like profiles and low-to-moderate predicted acute toxicity. Among the stable Mpro complexes, M2 displayed the strongest computed affinity (MM/GBSA ΔGbind = -38.8 kcal·mol ⁻ ¹), driven mainly by dispersion with limited desolvation cost, whereas M4 showed the most direct catalytic-dyad engagement through His41/Cys145-supported anchoring. DFT analysis rationalized these complementary profiles: M2 and M4 exhibited narrower HOMO-LUMO gaps (4.00 eV) and higher electronic softness, while ELF/NCI maps revealed heteroatom-centered electron reservoirs and weak intramolecular preorganization. The derived pharmacophore consists of a planar chromone π-platform bearing a carbonyl/phenolic acceptor-donor edge, a para-phenyl spacer for conjugation and hydrophobic occupancy, and a methoxy-tetrazole polar/π-rich head for Glu166/Phe140/His163 anchoring. Overall, M2 and M4 emerge as complementary lead chemotypes for experimental validation and structure-guided optimization against Mpro.

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