Identification of a novel chemical potentiator and inhibitors of UCH-L1 by in silico drug screening
Identification of a novel chemical potentiator and inhibitors of UCH-L1 by in silico drug screening
复制标题
DOI：
10.1016/j.neuint.2010.01.016
复制
发表时间：
2010-04-01
影响因子：
4.2
通讯作者：
Wada, Keiji
中科院分区：
文献类型：
--
作者：
Mitsui, Takeshi;Hirayama, Kazunori;Wada, Keiji
泛素 C 末端水解酶 L1 (UCH-L1) 是一种去泛素化酶，在大脑和生殖组织以及某些癌症中表达。 UCH-L1 的水解酶活性与阿尔茨海默病和癌症侵袭有关；因此，它可能代表这些疾病的治疗靶点。本研究旨在鉴定 UCH-L1 水解酶活性的新型化学调节剂。为了识别与 UCH-L1 活性位点结合的化学物质，我们使用人类 UCH-L1 晶体结构数据（PDB ID：2ETL）和包含 26,891 和 304,205 种化合物的虚拟化合物库进行了基于计算机结构的药物筛选。在结合得分最高的化合物中，我们确定了一种增强 UCH-L1 水解酶活性的化合物，以及六种抑制酶测定活性的化合物。这些化合物可能有助于研究 UCH-L1 功能，并可能成为 UCH-L1 相关疾病的候选疗法。 (C) 2010 Elsevier Ltd. 保留所有权利。
Ubiquitin-C-terminal hydrolase L1 (UCH-L1) is a de-ubiquitinating enzyme expressed in the brain and reproductive tissues as well as certain cancers. The hydrolase activity of UCH-L1 has been implicated in Alzheimer's disease and cancer invasion; therefore, it may represent a therapeutic target for these diseases. The present study was undertaken to identify novel chemical modulators for the hydrolase activity of UCH-L1. To identify chemicals that bind to the active site of UCH-L1, we carried out in silico structure-based drug screening using human UCH-L1 crystal structure data (PDB ID: 2ETL) and virtual compound libraries containing 26,891 and 304,205 compounds. Among the compounds with the highest binding scores, we identified one that potentiates the hydrolase activity of UCH-L1, and six that inhibit the activity in enzymatic assays. These compounds may be useful for research on UCH-L1 function, and could lead to candidate therapeutics for UCH-L1-associated diseases. (C) 2010 Elsevier Ltd. All rights reserved.