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dc.contributor.authorLi, Shuaizhang
dc.contributor.authorZhao, Jinghua
dc.contributor.authorHuang, Ruili
dc.contributor.authorTravers, Jameson
dc.contributor.authorKlumpp-Thomas, Carleen
dc.contributor.authorYu, Wenbo
dc.contributor.authorMacKerell, Alexander D
dc.contributor.authorSakamuru, Srilatha
dc.contributor.authorOoka, Masato
dc.contributor.authorXue, Fengtian
dc.contributor.authorSipes, Nisha S
dc.contributor.authorHsieh, Jui-Hua
dc.contributor.authorRyan, Kristen
dc.contributor.authorSimeonov, Anton
dc.contributor.authorSantillo, Michael F
dc.contributor.authorXia, Menghang
dc.date.accessioned2021-04-14T12:58:16Z
dc.date.available2021-04-14T12:58:16Z
dc.date.issued2021-04-12
dc.identifier.urihttp://hdl.handle.net/10713/15406
dc.description.abstractBackground: 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.en_US
dc.description.urihttps://doi.org/10.1289/EHP6993en_US
dc.language.isoenen_US
dc.publisherNational Institute of Environmental Health Sciencesen_US
dc.relation.ispartofEnvironmental Health Perspectivesen_US
dc.subjectTox21 10K Compound Libraryen_US
dc.subject.meshAcetylcholinesteraseen_US
dc.subject.meshCholinesterase Inhibitorsen_US
dc.titleProfiling the Tox21 Chemical Collection for Acetylcholinesterase Inhibitionen_US
dc.typeArticleen_US
dc.identifier.doi10.1289/EHP6993
dc.identifier.pmid33844597
dc.source.volume129
dc.source.issue4
dc.source.beginpage47008
dc.source.endpage
dc.source.countryUnited States


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