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Identification of a novel chemical potentiator and inhibitors of UCH-L1 by in silico drug screening.

机译:通过计算机药物筛选鉴定新型的UCH-L1化学增强剂和抑制剂。

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摘要

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.
机译:泛素C末端水解酶L1(UCH-L1)是在大脑和生殖组织以及某些癌症中表达的去泛素化酶。 UCH-L1的水解酶活性与阿尔茨海默氏病和癌症的侵袭有关。因此,它可以代表这些疾病的治疗目标。进行本研究以鉴定用于UCH-L1的水解酶活性的新型化学调节剂。为了鉴定结合UCH-L1活性位点的化学物质,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化合物的虚拟化合物库,进行了基于计算机模拟的药物筛选。在具有最高结合分数的化合物中,我们鉴定出一种可增强UCH-L1水解酶活性的化合物,另外六种可抑制酶促测定的活性。这些化合物可能对UCH-L1功能的研究有用,并可能导致UCH-L1相关疾病的候选治疗方法。

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