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.
Highlights
Melanin, a cluster of natural pigments, protects the skin by absorbing the harmful ultraviolet radiation (UVR) [1]
Melanogenesis is a process involving the catalysis of tyrosine by tyrosinase, tyrosinase-related protein 1 (TRP1), tyrosinase-related protein 2 (TRP2)/dopachrome tautomerase (DCT), and microphthalmia-associated transcription factor (MITF) [10,11]
Low-energy 3D structures of compounds in the in-house natural compound library were generated by LigPrep and docked into the active site of human tyrosinase model using Glide in the Standard Precision mode, based on a grid box of 20 × 20 × 20 Å3 centered on the co-crystallized ligand
Summary
A cluster of natural pigments, protects the skin by absorbing the harmful ultraviolet radiation (UVR) [1]. Since melanin is synthesized via a series of enzymatic reactions called melanogenesis, controlling the latter may revert the process as desired and lead to the identification of effective skin-whitening compounds for medicines and cosmetics [6,7,8,9]. Melanogenesis is a process involving the catalysis of tyrosine by tyrosinase, tyrosinase-related protein 1 (TRP1), tyrosinase-related protein 2 (TRP2)/dopachrome tautomerase (DCT), and microphthalmia-associated transcription factor (MITF) [10,11]. MITF is a major transcription factor that regulates melanogenic genes encoding tyrosinase and TRP2/DCT [12,13]. Tyrosinase is the rate-limiting enzyme catalyzing tyrosine, and TRP1 is responsible for the oxidation of 5,6-dihydroxyindole-2-carboxylic acid to a carboxylated indole quinone [14]. TRP2/DCT catalyze dopachrome to 5,6-dihydroxyindole-2-carboxylic acid [15]
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