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    Profiling the Tox21 Chemical Collection for Acetylcholinesterase Inhibition

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    Author
    Li, Shuaizhang
    Zhao, Jinghua
    Huang, Ruili
    Travers, Jameson
    Klumpp-Thomas, Carleen
    Yu, Wenbo
    MacKerell, Alexander D
    Sakamuru, Srilatha
    Ooka, Masato
    Xue, Fengtian
    Sipes, Nisha S
    Hsieh, Jui-Hua
    Ryan, Kristen
    Simeonov, Anton
    Santillo, Michael F
    Xia, Menghang
    Show allShow less

    Date
    2021-04-12
    Journal
    Environmental Health Perspectives
    Publisher
    National Institute of Environmental Health Sciences
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1289/EHP6993
    Abstract
    Background: Inhibition of acetylcholinesterase (AChE), a biomarker of organophosphorous and carbamate exposure in environmental and occupational human health, has been commonly used to identify potential safety liabilities. So far, many environmental chemicals, including drug candidates, food additives, and industrial chemicals, have not been thoroughly evaluated for their inhibitory effects on AChE activity. AChE inhibitors can have therapeutic applications (e.g., tacrine and donepezil) or neurotoxic consequences (e.g., insecticides and nerve agents). Objectives: The objective of the current study was to identify environmental chemicals that inhibit AChE activity using in vitro and in silico models. Methods: To identify AChE inhibitors rapidly and efficiently, we have screened the Toxicology in the 21st Century (Tox21) 10K compound library in a quantitative high-throughput screening (qHTS) platform by using the homogenous cell-based AChE inhibition assay and enzyme-based AChE inhibition assays (with or without microsomes). AChE inhibitors identified from the primary screening were further tested in monolayer or spheroid formed by SH-SY5Y and neural stem cell models. The inhibition and binding modes of these identified compounds were studied with time-dependent enzyme-based AChE inhibition assay and molecular docking, respectively. Results: A group of known AChE inhibitors, such as donepezil, ambenonium dichloride, and tacrine hydrochloride, as well as many previously unreported AChE inhibitors, such as chelerythrine chloride and cilostazol, were identified in this study. Many of these compounds, such as pyrazophos, phosalone, and triazophos, needed metabolic activation. This study identified both reversible (e.g., donepezil and tacrine) and irreversible inhibitors (e.g., chlorpyrifos and bromophos-ethyl). Molecular docking analyses were performed to explain the relative inhibitory potency of selected compounds. Conclusions: Our tiered qHTS approach allowed us to generate a robust and reliable data set to evaluate large sets of environmental compounds for their AChE inhibitory activity. https://doi.org/10.1289/EHP6993.
    Keyword
    Tox21 10K Compound Library
    Acetylcholinesterase
    Cholinesterase Inhibitors
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/15406
    ae974a485f413a2113503eed53cd6c53
    10.1289/EHP6993
    Scopus Count
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