Computational Study of Terpenes from Schinus molle L. Fruit Essential Oil as Potential Modulators of Osteoarthritis-Related Inflammatory Pathways: A Network Pharmacology and Molecular Docking Study

Abstract

This study investigated the effects of terpene compounds from Schinus molle fruit essential oil (EO) against osteoarthritis (OA) using integrated network pharmacology, molecular docking, and molecular dynamics. The EO, obtained by steam distillation (yield: 6.95%), was characterized by GC-MS, detecting 55 peaks (98.61% of the total), of which 49 were identified and dominated mainly by monoterpene hydrocarbons (73.93%), with α-phellandrene (20.35%), camphene (11.36%), and Z-β-ocimene (8.69%) as the major constituents. Additionally, seven compounds with favorable ADME profiles and low predicted toxicity were selected for the target prediction. Overlap analysis between compound targets and osteoarthritis-related genes (Os-teoDIP) revealed 171 common genes that triggered inflammatory pathways, including PI3K-Akt, HIF-1, and NOD-like receptor signaling. Protein–protein interaction network analysis identified 11 hub genes, including TLR4, HSP90AA1, PTGS2, and MAPK1. Molecular docking revealed that γ-cadinene exhibited the best binding affinities, particularly against HSP90AA1 (−6.38 kcal/mol) and TLR4 (−5.87 kcal/mol). A 200 ns molecular dynamics simulation confirmed the stability of the γ-cadinene–TLR4 complex through persistent hydrophobic contacts with residues F379, C391, F409, I310, and F377, with contact occupancy of up to 0.95. The receptor backbone RMSD plateaued between 2.5 and 3.5 Å after equilibration, and the ligand remained in the binding pocket throughout the trajectory. These findings suggest that the terpenes of S. molle EO, particularly γ-cadinene, may modulate the inflammatory pathways related to OA. However, it is necessary to complement experimental validation in vitro and in vivo.