Computational Evaluation of Fig-Derived Bioactive Compounds as COX-2 Inhibitors: Molecular Dynamics Reveals Desolvation-Driven Ranking Inversion Between Flavonoids and Furanocoumarins

Background. Figs ( Ficus carica ) have long been used in traditional medicine for anti-inflammatory effects, and they contain polyphenolic compounds with structural diversity across flavonoid and furanocoumarin scaffolds. Whether these compounds directly inhibit COX-2 — a key target in inflammation — has not been systematically tested with molecular dynamics and binding free-energy calculations. Methods. We applied a three-tier computational screening workflow to six fig-derived compounds (flavonoids: luteolin, quercetin; furanocoumarins: bergapten, psoralen; secoiridoid derivative: elenolic acid; phenol: hydroxytyrosol): (1) AutoDock Vina docking with smina/Vinardo scoring consensus; (2) 5 ns all-atom MD simulation (GROMACS 2026, CHARMM36 + GAFF2, 4 independent replicates per compound); (3) MM-GBSA binding free-energy calculation (igb = 2, saltcon = 0.150 M, gmx_MMPBSA v1.6.4) benchmarked against celecoxib. Structural reliability of the COX-2 template was verified by AlphaFold2 cross-validation (global RMSD 0.38 Å, pocket RMSD 0.25 Å vs AF-P35354-F1 raw prediction). Oleocanthal from the companion study served as an upper-bound reference. Two glycoside compounds (oleuropein, rutin) underwent docking only due to force-field conversion limitations. Results. All six tested fig-derived compounds bound less favourably than celecoxib in this computational model (ΔΔG range: +18.6 to + 28.5 kcal mol⁻¹, Welch t-test p ≤ 8.5×10⁻⁷ for all comparisons), suggesting that none of the compounds screened here approaches celecoxib-level COX-2 active-site affinity under these conditions. Within the test panel, furanocoumarins ranked above flavonoids: bergapten (ΔΔG = + 18.56 vs celecoxib; absolute ΔG = − 20.32 ± 0.97 kcal mol⁻¹) and psoralen (ΔΔG = + 19.93; −18.95 ± 1.16) outranked luteolin (− 16.54 ± 0.88) and quercetin (− 14.36 ± 1.53) despite weaker Vina docking scores — a desolvation-driven ranking inversion. Elenolic acid (− 14.88 ± 1.02) and hydroxytyrosol (− 10.34 ± 0.56) were the weakest binders. Although bergapten and psoralen show the strongest fig-derived binding in this model, both are known CYP3A4 inhibitors and phototoxic agents, raising concerns that would limit their direct therapeutic use. Conclusions. This computational screening phase indicates that none of the six tested fig-derived compounds approaches celecoxib potency at the COX-2 active site in this model, suggesting that experimental focus for fig bioactives may be better directed toward alternative anti-inflammatory mechanisms. The desolvation-driven ranking inversion between furanocoumarins and flavonoids is a methodologically important finding: Vina docking scores would have predicted flavonoids as the stronger binders, while physics-based MM-GBSA correctly captures the desolvation penalty that reverses this ranking — demonstrating why single-tier docking is insufficient for polar natural products. All raw data are deposited on Zenodo for full reproducibility.