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Profiling the Tox21 Chemical Collection for Acetylcholinesterase Inhibition
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 additi...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Environmental Health Perspectives
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041433/ https://www.ncbi.nlm.nih.gov/pubmed/33844597 http://dx.doi.org/10.1289/EHP6993 |
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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 |
author_facet | 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 |
author_sort | Li, Shuaizhang |
collection | PubMed |
description | 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 |
format | Online Article Text |
id | pubmed-8041433 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Environmental Health Perspectives |
record_format | MEDLINE/PubMed |
spelling | pubmed-80414332021-04-13 Profiling the Tox21 Chemical Collection for Acetylcholinesterase Inhibition 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 Environ Health Perspect Research 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 Environmental Health Perspectives 2021-04-12 /pmc/articles/PMC8041433/ /pubmed/33844597 http://dx.doi.org/10.1289/EHP6993 Text en https://ehp.niehs.nih.gov/about-ehp/licenseEHP is an open-access journal published with support from the National Institute of Environmental Health Sciences, National Institutes of Health. All content is public domain unless otherwise noted. |
spellingShingle | Research 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 Profiling the Tox21 Chemical Collection for Acetylcholinesterase Inhibition |
title | Profiling the Tox21 Chemical Collection for Acetylcholinesterase Inhibition |
title_full | Profiling the Tox21 Chemical Collection for Acetylcholinesterase Inhibition |
title_fullStr | Profiling the Tox21 Chemical Collection for Acetylcholinesterase Inhibition |
title_full_unstemmed | Profiling the Tox21 Chemical Collection for Acetylcholinesterase Inhibition |
title_short | Profiling the Tox21 Chemical Collection for Acetylcholinesterase Inhibition |
title_sort | profiling the tox21 chemical collection for acetylcholinesterase inhibition |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041433/ https://www.ncbi.nlm.nih.gov/pubmed/33844597 http://dx.doi.org/10.1289/EHP6993 |
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