Tyrosinase-Targeting Gallacetophenone Inhibits Melanogenesis in Melanocytes and Human Skin- Equivalents

Abstract

Demands for safe depigmentation compounds are constantly increasing in the pharmaceutical and cosmetic industry, since the numerous relevant compounds reported to date have shown undesirable side effects or low anti-melanogenic effects. In this study, we reported three novel inhibitors of tyrosinase, which is the key enzyme in melanogenesis, identified using docking-based high throughput virtual screening of an in-house natural compound library followed by mushroom tyrosinase inhibition assay. Of the three compounds, gallacetophenone showed high anti-melanogenic effect in both human epidermal melanocytes and a 3D human skin model, MelanoDerm. The inhibitory effect of gallacetophenone on tyrosinase was elucidated by computational molecular modeling at the atomic level. Binding of gallacetophenone to the active site of tyrosinase was found to be stabilized by hydrophobic interactions with His367, Ile368, and Val377; hydrogen bonding with Ser380 and a water molecule bridging the copper ions. Thus, our results strongly suggested gallacetophenone as an anti-melanogenic ingredient that inhibits tyrosinase.

Antimelanogenesis Effects of Theasinensin A

“…These results indicate that TSA regulates melanin secretion and intracellular melanin content in B16F10 cells by inhibiting the cAMP pathway. Tyrosinases are mediated in this process, and it is thought that the suppression of tyrosinase activity is an effective strategy for the suppression of melanin formation [ 1 , 36 ].…”

In silico ADMET, molecular docking and molecular simulation-based study of glabridin’s natural and semisynthetic derivatives as potential tyrosinase inhibitors

“…However, differences in the binding pockets of mushroom and human tyrosinase have been reported (Garcia -Borron, 2002 ). Only few researchers have reported modelling of human tyrosinase enzyme (Lee et al, 2020 ; Nokinsee et al 2015 ) but in their modelling studies, the template similarity was very low. Nokinsee et al ( 2015 ) used protein template, tyrosinase of B. megaterium (PDB Id- 3NQ1) which had highest identity with human tyrosinase of only 33.5%, whereas in present study template used for homology modelling is Human tyrosinase related protein (PDB ID 5M8Q) which showed 44.6% identity with hTYR.…”

“…The most prominent approach for the development of melanogenesis inhibitors is the down regulation of tyrosinase as strong correlation has been observed between tyrosinase and melanin pigmentation (Masum et al 2019 ; Pillaiyar et al 2017 ). Targeting tyrosinase is the key to comprehend the knowledge of melanin inhibition mechanism which can help to improve hyper pigmentary conditions (Lee et al 2020 ). Several tyrosinase inhibitors are reported as potential therapeutic and cosmetic agents for various hyperpigmentation conditions and skin related issues respectively.…”

In silico ADMET, molecular docking and molecular simulation-based study of glabridin’s natural and semisynthetic derivatives as potential tyrosinase inhibitors

“…The most prominent approach for the development of melanogenesis inhibitors is the down regulation of tyrosinase as strong correlation has been observed between tyrosinase and melanin pigmentation (Masum et al, 2019;Pillaiyer et al, 2017). Targeting tyrosinase is the key to comprehend the knowledge of melanin inhibition mechanism which can help to improve hyper pigmentary conditions (Lee et al, 2020). Several tyrosinase inhibitors are reported as potential therapeutic and cosmetic agents for various hyperpigmentation conditions and skin related issues respectively.…”