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

• Published in: Neurochemistry international 2010-04, Vol.56 (5), p.679-686
• Main Authors: Mitsui, Takeshi, Hirayama, Kazunori, Aoki, Shunsuke, Nishikawa, Kaori, Uchida, Kenko, Matsumoto, Takashi, Kabuta, Tomohiro, Wada, Keiji
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Biological and medical sciences; Cancer; Computer Simulation; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Drug Evaluation, Preclinical; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; Fundamental and applied biological sciences. Psychology; Gene Library; Humans; In silico; Indicators and Reagents; Inhibitor; Inhibitory Concentration 50; Kinetics; Ligands; Medical sciences; Models, Molecular; Neurology; Potentiator; Protein Binding; Protein Conformation; Structure-Activity Relationship; Substrate Specificity; Ubiquitin Thiolesterase - antagonists & inhibitors; Ubiquitin Thiolesterase - chemistry; Ubiquitin Thiolesterase - metabolism; Ubiquitin-C-terminal hydrolase L1 (UCH-L1); Vertebrates: nervous system and sense organs
• ISSN: 0197-0186; 1872-9754
• DOI: 10.1016/j.neuint.2010.01.016

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.