Computational evaluation of synergistic inhibitors for human tyrosinase: multiple-ligand docking and molecular dynamics study

Human tyrosinase (hsTYR) is a key enzyme in melanogenesis, catalyzing the conversion of L-tyrosine to dopaquinone. Limited structural data on hsTYR, has led the use of mushroom tyrosinase (abTYR) as a surrogate in drug development, despite significant differences in active site interactions and inhibition mechanisms. This study aims to overcome this limitation by directly identifying and evaluating potential hsTYR inhibitors using a comprehensive computational approach. A total of 172 synthetic and natural compounds were screened via molecular docking against the hsTyr1 complex with Tropolone (PDB: 5M8O) using PLANTS software. Among the screened compounds, the combination of compound 38c and compound 42 yielded the most favorable docking score (−86.30 ± 0.61), indicating strong synergistic inhibition potential. Molecular dynamic simulations further evaluated selected combinations, revealing improved binding stability, enhanced hydrogen bond occupancy, and synergistic interaction patterns. This strategy highlights the potential for developing effective tyrosinase inhibitors, directly targeting hsTYR for therapeutic and cosmetic applications.