In Silico Evaluation and ADMET Profiling of Silybum marianum Bioactive Compounds as Selective COX-2 Inhibitors

Abstract

Long-term administration of selective COX-2 inhibitors from synthetic sources faces restrictions owing to adverse effects on cardiovascular and digestive system, maintaining the focus on designing different and natural compounds which would exhibit better isoform selectivity. Silybum marianum is abundant with various flavonolignan and flavonoid phytoconstituents which have shown some anti-inflammatory effect; however, their potential for isoform-specific selectivity of binding to COX-2 enzyme and oral bioavailability still needs to be investigated systematically. To compare S. marianum phytoconstituents regarding their selectivity towards COX-1/COX-2 isoforms, active site interactions and pharmacokinetic/toxicological characteristics compared to nine NSAID and coxib drugs. Docking of twelve phytoconstituents was performed against COX-2 enzyme and its counterpart COX-1 enzyme using PyRx 0.8/AutoDock Vina. The degree of isoform selectivity was calculated through SI (Selectivity Index) and hierarchical clustering by Z-score normalization method. Pose reproducibility was evaluated using RMSD distance between separate docking experiments aligned in PyMOL. ADMET analysis and druglikeness were predicted through SwissADME while toxicity with ProTox-II. Taxifolin (ΔG = −9.8 kcal/mol; SI = 1.13) and quercetin (ΔG = −9.7 kcal/mol; SI = 1.10) were the only phytoconstituents demonstrating COX-2 selective efficacy equivalent to clinically used coxibs (SI 1.13-1.27), stabilized by conserved interactions with Ser339 and Val509 resembling those in the binding pocket of celecoxib. Furthermore, taxifolin and quercetin possessed high oral bioavailability and Lipinski compliance, unlike larger flavonolignans, which suffered from a high topological polar surface area (TPSA > 150 Ų). The majority of phytoconstituents had a low toxicity profile (LD₅₀ ≥ 2000 mg/kg), with the exception of quercetin (LD₅₀ = 159 mg/kg). Thus, taxifolin and quercetin can be considered structurally validated and pharmacokinetically suitable anti-inflammatory drug candidates targeting COX-2, providing an alternative approach from common silymarin formulations.