In vitro tyrosinase inhibitory activity and molecular docking studies of major terpenic compounds from Pistacia lentiscus leaf essential oils

Tyrosinase, a copper-dependent oxidase, catalyzes the rate-limiting steps of melanin biosynthesis and represents a key target for skin-whitening cosmetics. This study evaluated the anti-tyrosinase activity of Pistacia lentiscus leaf essential oils (EOs) and performed molecular docking of their major terpenic constituents. Leaves were collected from four Tunisian regions (Testour, Beni Mtir, Nefza, Jbel Mghila) during the flowering stage. Hydrodistillation yielded 0.03–0.08 % (w/w) EOs, with Testour recording the highest value. GC–MS analysis identified 77 volatile compounds, dominated by germacrene-D, δ-cadinene, and β-caryophyllene. Regional variations were pronounced: monoterpene hydrocarbons predominated in Nefza (66.28 %), sesquiterpene hydrocarbons in Beni Mtir (53.20 %), oxygenated monoterpenes in Testour (18.15 %), and oxygenated sesquiterpenes in Jbel Mghila and Beni Mtir (≈8.5–8.7 %). In vitro assays against mushroom tyrosinase showed moderate, dose-dependent inhibition by the EOs (IC₅₀ 747.0 ± 0.01 –872.0 ± 0.002 µg/ml), compared with kojic acid (18.0 ± 2.77 µg/ml). Molecular docking analysis showed that the selected terpene (D-limonene, α-pinene, δ-cadinene, and β-caryophyllene) exhibited binding affinities ranging from −4.69 to −5.90 kcal/mol toward mushroom tyrosinase and human tyrosinase related protein 1 (T391V-R374S-Y362F), as determined using Molecular Operating Environment (MOE). Among them, δ-cadinene and β-caryophyllene showed the most favorable binding, supported by non-polar/van der Waals contacts within the active site, consistent with hydrophobic pocket occupancy rather than classical hydrogen bonding or metal coordination. In contrast, multiple-ligand simultaneous docking (MLSD) performed with AutoDock Vina 1.2.7 indicated predominantly unfavorable interactions between the terpenes, suggesting limited cooperative binding. Thus, the present in silico study provides deeper insight into the structural characteristics of the studied compounds and their molecular interactions with mushroom tyrosinase and human tyrosinase related protein 1 (T391V-R374S-Y362F).