Improving quercetin solubility via structural modification enhances dual-target coronavirus entry: an integrated in-vitro and in-silico study

The modified quercetin derivatives have recently emerged as promising therapeutic candidates, as the ongoing COVID-19 pandemic continues to underscore the urgent need for potent antiviral agents. We hypothesized that quercetin penta-phosphate (QPP) and quercetin para-aminobenzoic acid (QPABA) could act as potential inhibitors of spike protein-receptor binding and accordingly synthesized and characterized them. ELISA assays demonstrated that QPABA exhibited the most potent inhibitory activity, with IC50 values of 12.02 µM and 14.4 µM for DPP4–MERS-CoV and ACE2-SARS-CoV-2-spike complex, respectively (p values < 0.0005). Consistently, molecular docking and molecular dynamics simulations revealed that QPABA exhibited the strongest binding affinity among all tested compounds, showing the lowest binding energy (− 10.2 kcal/mol) toward the DPP4-MERS-CoV spike complex by disrupting the key electrostatic interaction between DPP4 residue K267 and viral residue D539. A similarly strong interaction was observed with the ACE2–SARS-CoV-2 spike complex (− 9.4 kcal/mol), through blocking hotspot residues (F456, Y489, I472, and L492). Additionally, physicochemical and pharmacokinetic properties of QPABA and QPP were evaluated by POM analysis, supporting their potential for therapeutic development. While QPP offers improved aqueous behavior for formulation versatility, QPABA demonstrates strong spike–receptor interactions suitable for next-generation antiviral agent development.