INTEGRATIVE IN SILICO DRUG DISCOVERY: TARGETING TYROSINASE WITH NATURAL COMPOUNDS FOR THERAPEUTIC MANAGEMENT OF VITILIGO

Abstract

Vitiligo is a complex skin condition marked by the progressive disappearance of melanocytes, the pigment-producing cells of the epidermis. This results in irregular white patches on the skin which significantly affect a patient’s quality of life. Despite various clinical interventions ranging from topical agents to phototherapy, current treatments frequently fall short in terms of consistency and safety. Among the biomolecular targets implicated in pigment biosynthesis, tyrosinase—a critical enzyme in melanin production—has emerged as a focal point for therapeutic intervention. This research investigates the potential of select natural compounds to modulate tyrosinase activity using an integrated in silico framework. The study follows a structured methodology that combines molecular docking, pharmacokinetic filtering and molecular dynamics simulation to evaluate and validate efficacy of the compounds (ligands). The three-dimensional structure of tyrosinase was retrieved and prepared for docking studies. A curated list of natural compounds—including Hinokinin, Lichexanthone, Tabernaemontanine, Dregamine, and Herboxidiene—was examined for binding potential. Using AutoDock, these compounds were docked to the active site of the enzyme. Binding site residues were predicted through PrankWeb, while interactions were analyzed using tools such as LigPlot and Protein Plus. Docking poses were refined and assessed based on root-mean-square deviation clustering and binding conformation stability. To assess the pharmacological viability of each compound, a series of ADME (Absorption, Distribution, Metabolism, and Excretion) evaluations were conducted via the SwissADME platform. These analyses helped identify candidates with favourable properties such as high intestinal absorption, blood-brain barrier permeability and minimal inhibitory effects on cytochrome P450 enzymes. Compounds that met these pharmacokinetic criteria proceeded to molecular dynamics simulations, run over a 5 ns period using a cloud-based system, to capture their behaviour in a biologically relevant environment. From the set of compounds studied, Hinokinin and Tabernaemontanine emerged as strong candidates, exhibiting high binding affinity, favourable ADME profiles and structural stability in dynamic simulation environments. While Dregamine and Herboxidiene also showed meaningful interaction with tyrosinase, they demonstrated relatively less structural retention during simulation. Lichexanthone, though modest in docking score, displayed pharmacokinetic advantages and sustained simulation stability, supporting its inclusion for future development. This study underscores the value of computational modelling in early-stage drug discovery, particularly in dermatological applications. The integration of docking, pharmacokinetics and dynamic simulations presents a comprehensive route to filter promising candidates before experimental trials. In addition to contributing potential leads for vitiligo therapy, this research framework may be adapted for broader applications in targeting melanin-associated disorders. Looking ahead, these computational insights require experimental validation to substantiate therapeutic utility. Follow-up studies involving biochemical assays, cell-based models and eventually animal trials will be critical in determining efficacy and safety. Further, structure activity relationship (SAR) analysis and derivatization of lead compounds may help enhance target specificity. Expanding the natural compound library and applying AI-driven predictive screening could also accelerate discovery. Ultimately, this research offers a foundation for 6 developing natural, plant-based, non-toxic therapeutic options that address the clinical gap in vitiligo treatment.