Enhanced tyrosinase inhibitory activity of side chain-modified aromatic-turmerone derived from Curcuma longa for advanced skin whitening formulations

Tyrosinase (TYR) is a key enzyme in melanin production and a crucial target for skin-whitening agents. Due to challenges in isolating pure human TYR, we constructed a homology model and evaluated the inhibitory effects of Ar-turmerone (A1) and its derivatives (A8 and B18) through in vitro assays and molecular dynamics (MD) simulations. Ar-turmerone reduced TYR activity by 19.2 % at 2.0 × 10⁻⁴ M, while bromine- and indole-modified turmerone (B18) exhibited the highest binding energy (−85.27 ± 15.73 kJ/mol). A DPPC lipid bilayer model revealed that indole modification enhances skin permeability by reducing the energy barrier by 11 kJ/mol. Methyl substitution increased binding free energy by 14.7 %. Our findings demonstrate that Ar-turmerone inhibits tyrosinase to prevent melanin synthesis and that rational side-chain modifications enhance both activity and permeability. This study provides mechanistic insights into Ar-turmerone's potential as a skin-whitening agent, guiding future food-derived drug development.