In Silico Evaluation of Terpene Interactions with Inflammatory Enzymes: A Blind Docking Study Targeting Arachidonic Acid Metabolism

Terpenes represent a structurally diverse class of natural compounds with increasing scientific interest due to their potential anti-inflammatory properties. This study investigates the in silico binding behavior of six plant-derived terpenes—α-pinene, β-pinene, menthol, camphor, limonene, and linalool—against four key enzymes in the arachidonic acid (AA) metabolic pathway: cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX), and phospholipase A2 (PLA2). AA serves as a reference for binding energy comparison. Blind rigid-body molecular docking is performed using AutoDock 4.2 and the Lamarckian Genetic Algorithm, with 100 runs per ligand–enzyme pair and the energy-based selection of optimal poses. The analysis includes binding energy (ΔG), inhibition constants (Ki), root-mean-square deviation (RMSD), and residue-level interactions. Several terpenes exhibit favorable binding energies and inhibition constants across the evaluated enzymes. For COX-1 and COX-2, menthol and camphor show low Ki values, indicating stable binding. Menthol and limonene also show the strongest affinities for PLA2, exceeding AA. The focus is on compounds with potential to modulate arachidonic acid metabolism. In this context, β-pinene engages the catalytic site of PLA2, linalool forms multiple contacts within key regions of 5-LOX, and menthol, α-pinene, and β-pinene align with functionally important regions in both COX isoforms. These targeted interactions suggest that the highlighted compounds may selectively interfere with enzymatic activity in inflammation-related pathways. By modulating key steps in AA metabolism, these terpenes may influence the biosynthesis of pro-inflammatory mediators, offering a promising avenue for the development of safer, plant-derived anti-inflammatory agents. The findings lay the groundwork for further experimental validation and the structure-based optimization of terpene-derived modulators.