Institute for Theoretical Medicine, Inc., 4259-3 Nagatsuda-cho, Midori-ku, Yokohama 226-8510, Japan.
Bioorg Med Chem. 2010 Nov 15;18(22):8112-8. doi: 10.1016/j.bmc.2010.08.056. Epub 2010 Oct 12.
Tyrosinase inhibitors are important agents for cosmetic products. We examined here the inhibitory effects of three isomers of thujaplicins (α, β and γ) on mushroom tyrosinase and analyzed their binding modes using a homology model from the crystal structure of Streptomyces castaneoglobisporus tyrosinase (PDB ID: 1wx2). All the thujaplicins were found to be competitive inhibitors and γ-thujaplicin has the most potent inhibitory activity (IC(50)=0.07μM). It is noted that there are good correlations between their observed IC(50) values and their binding free energies calculated by MM-GB/SA. The binding modes of thujaplicins were predicted to be similar to that of Tyr98 of caddie protein (ORF378), which was co-crystallized with S. castaneoglobisporus tyrosinase. Furthermore, free energy decomposition analysis indicated that the potent inhibitory activity of γ-thujaplicin is due to the interactions with His242, Val243 and Pro257 (hot spot amino acid residues) at the active site of tyrosinase. These results provide a novel structural insight into the hot spot of mushroom tyrosinase for the specific binding of γ-thujaplicin.
酪氨酸酶抑制剂是化妆品的重要成分。我们研究了三种土木香倍半萜内酯（α、β 和 γ）对蘑菇酪氨酸酶的抑制作用，并利用来自链霉菌土生黄单胞菌酪氨酸酶（PDB ID：1wx2）晶体结构的同源模型分析了它们的结合模式。结果发现所有的土木香倍半萜内酯都是竞争性抑制剂，而 γ-土木香倍半萜内酯具有最强的抑制活性（IC50=0.07μM）。值得注意的是，它们的观察到的 IC50 值与其通过 MM-GB/SA 计算的结合自由能之间存在很好的相关性。预测土木香倍半萜内酯的结合模式与与链霉菌土生黄单胞菌酪氨酸酶共结晶的 caddie 蛋白（ORF378）的 Tyr98 相似。此外，自由能分解分析表明，γ-土木香倍半萜内酯的强抑制活性归因于与酪氨酸酶活性位点的 His242、Val243 和 Pro257（热点氨基酸残基）的相互作用。这些结果为 γ-土木香倍半萜内酯与蘑菇酪氨酸酶的特定结合提供了一个新的结构见解。
