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

Abstract

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.

• Authors: Takeshi Mitsui, Kazunori Hirayama, Shunsuke Aoki, Kaori Nishikawa, Kenko Uchida, Takashi Matsumoto, Tomohiro Kabuta, Keiji Wada
• Journal: Neurochemistry international (Neurochem Int) Vol. 56 Issue 5 Pg. 679-86 (Apr 2010) ISSN: 1872-9754 [Electronic] England
• PMID: 20144674 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Indicators and Reagents
• Ligands
• UCHL1 protein, human
• Ubiquitin Thiolesterase

Topics

• Computer Simulation
• Drug Evaluation, Preclinical
• Enzyme Inhibitors (chemistry, metabolism, pharmacology)
• Gene Library
• Humans
• Indicators and Reagents
• Inhibitory Concentration 50
• Kinetics
• Ligands
• Models, Molecular
• Protein Binding
• Protein Conformation
• Structure-Activity Relationship
• Substrate Specificity
• Ubiquitin Thiolesterase (antagonists & inhibitors, chemistry, metabolism)