Highly potent tyrosinase inhibitor, neorauflavane from Campylotropis hirtella and inhibitory mechanism with molecular docking

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• 作者：Xuefei Tan^a ; Yeong Hun Song^a ; Chanin Park^b ; Ki-Won Lee^b ; Jeong Yoon Kim^a ; Dae Wook Kim^a ; Kwang Dong Kim^b ; Keun Woo Lee^b ; Marcus J. Curtis-Long^c ; Ki Hun Park^a ; ^{khpark@gnu.ac.kr" class="auth_mail" title="E-mail the corresponding author}
• 关键词：IC50 ; the inhibitor concentration leading 50% activity loss ; Ki ; inhibition constant ; Kiapp ; apparent Ki ; K ; rate constant ; Vmax ; maximum velocity ; Km ; Michaelis&minus ; Menten constant ; Kobs ; apparent first-order rate constant for the transition from νi to νs ; νi ; initial velocity ; νs ; steady-state rate
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：15 January 2016
• 年：2016
• 卷：24
• 期：2
• 页码：153-159
• 全文大小：1130 K

文摘

Tyrosinase inhibition may be a means to alleviate not only skin hyperpigmentation but also neurodegeneration associated with Parkinson’s disease. In the course of metabolite analysis from tyrosinase inhibitory methanol extract (80% inhibition at 20 μg/ml) of Campylotropis hirtella, we isolated fourteen phenolic compounds, among which neorauflavane dFont">3 emerged as a lead structure for tyrosinase inhibition. Neorauflavane dFont">3 inhibited tyrosinase monophenolase activity with an IC₅₀ of 30 nM. Thus this compound is 400-fold more active than kojic acid. It also inhibited diphenolase (IC₅₀ = 500 nM), significantly. Another potent inhibitor dFont">1 (IC₅₀ = 2.9 μM) was found to be the most abundant metabolite in C. hirtella. In kinetic studies, compounds dFont">3 showed competitive inhibitory behavior against both monophenolase and diphenolase. It manifested simple reversible slow-binding inhibition against monophenolase with the following kinetic parameters: K_i^app = 1.48 nM, k₃ = 0.0033 nM^−1 min^−1 and k₄ = 0.0049 min^−1. Neorauflavane dFont">3 efficiently reduced melanin content in B16 melanoma cells with 12.95 μM of IC₅₀. To develop a pharmacophore model, we explored the binding mode of neuroflavane dFont">3 in the active site of tyrosinase. Docking results show that resorcinol motif of B-ring and methoxy group in A-ring play crucial roles in the binding the enzyme.