化学
酪氨酸酶
帕金森病
药物发现
药理学
生物化学
酶
疾病
内科学
医学
作者
Shulei Qi,Linjie Guo,Jinxin Liang,Kaixuan Wang,Qinghong Liao,Siyu He,Weiping Lyu,Zimeng Cheng,Jiayi Wang,Xiaojia Luo,Xiaomei Yan,Ziyao Lu,Xiaohan Wang,Ziming Wang,Xuehong Chen,Qi Li
标识
DOI:10.1016/j.bioorg.2024.107612
摘要
The high level of tyrosinase leads to the generation of neuromelanin, further causing the abnormality of redox-related protein level and mediating the occurrence and development of Parkinson's disease (PD). However, the existing tyrosinase inhibitors are mostly natural product extracts or polyphenolic derivatives, which hindered them from penetrating the blood–brain barrier (BBB). Herein, we obtained a novel tyrosinase inhibitor, 2-06 (tyrosinase: monophenolase IC50 = 70.44 ± 22.69 μM, diphenolase IC50 = 1.89 ± 0.64 μM), through the structure-based screening method. The compound 2-06 presented good in vitro and in vivo safety, and can inhibit the tyrosinase and melanogenesis in B16F10. Moreover, this compound showed neuroprotective effects and Parkinsonism behavior improving function. 2-06 was proved to penetrate the BBB and enter the central nervous system (CNS). The exploration of the binding mode between 2-06 and tyrosinase provided the foundation for the subsequent structural optimization. This is the first research to develop a central-targeting tyrosinase inhibitor, which is crucial for in-depth study on the new strategy for utilizing tyrosinase inhibitors to treat PD.
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