In September 2025, the latest collaborative work of DIVAMICS and Wuhan University of Technology, entitled “Theoretical studies of arbutin, glutathione, and sea cucumber extracts as inhibitors of tyrosinase”, was published in the international journal Scientific Reports. In this study, the team leveraged the AlphaFold3-predicted structure of human tyrosinase (hTYR) and combined molecular docking with long-timescale molecular dynamics (MD) simulations to analyze, at atomic resolution, how natural whitening ingredients interact specifically with hTYR. The study addresses the technical limitations of using mushroom tyrosinase (mTYR) as a surrogate model and provides a scientific basis for designing effective and safer tyrosinase inhibitors.

Industry context: structural limitations of surrogate models constrain precision R&D

Tyrosinase is the rate-limiting enzyme in melanin production and a central target in the development of skin-whitening ingredients. Because human tyrosinase (hTYR) is difficult to isolate and its crystal structure remains unresolved, researchers have long relied on mushroom tyrosinase (mTYR) as a model enzyme to evaluate inhibitor activity.

However, sequence and structural comparisons reveal substantial divergence between hTYR and mTYR. The sequence identity between mTYR and hTYR is only 25%, and the identity of residues within 12 Å of the copper ions in the active pocket is only 11.8%, with an overall similarity of about 23.5%. The pocket surface of hTYR contains more acidic amino acids, such as Asp167, Asp178, Asp180, Asp286, and Glu184, giving it a more hydrophilic character, whereas the mTYR pocket is enriched in hydrophobic residues and presents a different exposure pattern of the copper-binding region.

These differences can lead to fundamentally distinct binding preferences for inhibitors. For example, compounds such as kojic acid show promising inhibitory effects when evaluated on mTYR but exhibit adverse reactions, including contact dermatitis, when used in humans and are banned in certain markets such as Switzerland. Hydroquinone, another classical ingredient, has been restricted in multiple countries due to serious side effects.

Because the key functional regions of mTYR and hTYR are not fully conserved, compounds screened solely on mTYR may show off-target effects when translated to human applications, making it difficult to fully mitigate safety risks.