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

Takeshi Mitsui, Kazunori Hirayama, Shunsuke Aoki, Kaori Nishikawa, Kenko Uchida, Takashi Matsumoto, Tomohiro Kabuta, Keiji Wada

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    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.

    Original languageEnglish
    Pages (from-to)679-686
    Number of pages8
    JournalNeurochemistry International
    Volume56
    Issue number5
    DOIs
    Publication statusPublished - 2010 Apr

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    Keywords

    • Alzheimer's disease
    • Cancer
    • In silico
    • Inhibitor
    • Potentiator
    • Ubiquitin-C-terminal hydrolase L1 (UCH-L1)

    ASJC Scopus subject areas

    • Cellular and Molecular Neuroscience
    • Cell Biology

    Cite this

    Mitsui, T., Hirayama, K., Aoki, S., Nishikawa, K., Uchida, K., Matsumoto, T., Kabuta, T., & Wada, K. (2010). Identification of a novel chemical potentiator and inhibitors of UCH-L1 by in silico drug screening. Neurochemistry International, 56(5), 679-686. https://doi.org/10.1016/j.neuint.2010.01.016