کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
1361888 981473 2007 9 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Identification of novel chemical inhibitors for ubiquitin C-terminal hydrolase-L3 by virtual screening
موضوعات مرتبط
مهندسی و علوم پایه شیمی شیمی آلی
پیش نمایش صفحه اول مقاله
Identification of novel chemical inhibitors for ubiquitin C-terminal hydrolase-L3 by virtual screening
چکیده انگلیسی

UCH-L3 (ubiquitin C-terminal hydrolase-L3) is a de-ubiquitinating enzyme that is a component of the ubiquitin–proteasome system and known to be involved in programmed cell death. A previous study of high-throughput drug screening identified an isatin derivative as a UCH-L3 inhibitor. In this study, we attempted to identify a novel inhibitor with a different structural basis. We performed in silico structure-based drug design (SBDD) using human UCH-L3 crystal structure data (PDB code; 1XD3) and the virtual compound library (ChemBridge CNS-Set), which includes 32,799 chemicals. By a two-step virtual screening method using DOCK software (first screening) and GOLD software (second screening), we identified 10 compounds with GOLD scores of over 60. To address whether these compounds exhibit an inhibitory effect on the de-ubiquitinating activity of UCH-L3, we performed an enzymatic assay using ubiquitin-7-amido-4-methylcoumarin (Ub-AMC) as the substrate. As a result, we identified three compounds with similar basic dihydro-pyrrole skeletons as UCH-L3 inhibitors. These novel compounds may be useful for the research of UCH-L3 function, and in drug development for UCH-L3-associated diseases.

A UCH-L3 inhibitor (1-benzyl-3-hydroxy-4-(5-methyl-2-furoyl)-5-(3-pyridinyl)-1,5-dihydro-2H-pyrrol-2-one) identified by virtual screening is shown.Figure optionsDownload as PowerPoint slide

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry - Volume 15, Issue 21, 1 November 2007, Pages 6810–6818
نویسندگان
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