Abstract
Tyrosinase is an oxidase that is the rate-limiting enzyme for controlling the production of melanin in the human body. Overproduction of melanin can lead to a variety of skin disorders. Calycosin is an isoflavone from Astragali Radix, which is a traditional Chinese medicine that exhibits several pharmacological activities including skin whitening. In our study, the inhibitory effect of calycosin on melanin production is confirmed in a zebrafish in vivo model by comparing with hydroquinone, kojic acid, and arbutin, known as tyrosinase inhibitors. Moreover, the inhibitory kinetics of calycosin on tyrosinase and their binding mechanisms are determined using molecular docking techniques, molecular dynamic simulations, and free energy analysis. The results indicate that calycosin has an obvious inhibitory effect on zebrafish pigmentation at the concentration of 7.5 μM, 15 μM, and 30 μM. The IC50 of calycosin is 30.35 μM, which is lower than hydroquinone (37.35 μM), kojic acid (6.51 × 103 μM), and arbutin (3.67 × 104 μM). Furthermore, all the results of molecular docking, molecular dynamics simulations, and free energy analysis suggest that calycosin can directly bind to the active site of tyrosinase with very good binding affinity. The study indicates that the combination of computer molecular modeling and zebrafish in vivo assay would be feasible in confirming the result of the in vitro test and illustrating the target-binding information.
Highlights
Melanin pigment has several functions, including protection of the skin from ultraviolet light and removal of reactive oxygen species [1,2]
The result of quantitative analysis on the integrated optical density (IOD) value of the whole fish body (Figure 3.) indicated that 7.5, 15, and 30 μM calycosin could significantly inhibit 21%, 26%, and 52% (p < 0.001) of the IOD value compared to the blank control group
The IC50 of calycosin, hydroquinone, kojic acid, and arbutin on pigment production inhibition was calculated as 30.35 μM, 37.35 μM, 6.51 × μM, and 3.67 × μM (Table 1), which suggested that calycosin was as effective as Hydroquinone in inhibiting zebrafish pigmentation
Summary
Melanin pigment has several functions, including protection of the skin from ultraviolet light and removal of reactive oxygen species [1,2]. Excessive production of melanin pigment and its accumulation in the skin can cause pigmentation disorders, such as solar lentigo, melasma, freckles, and post-inflammatory hyperpigmentation [3,4]. Tyrosinase is a copper-containing enzyme that catalyzes two distinct reactions of melanin synthesis: the hydroxylation of a monophenol and the conversion of an O-diphenol to the corresponding O-quinone. In these oxidation reactions, three different forms of binuclear copper are involved in the active site [7]. Tyrosinase inhibitors have become increasingly important in medicinal and cosmetic products in relation to hyperpigmentation [8]. Searching for tyrosinase inhibitors with higher bioactivity and lower toxicity has become a hot research topic
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