The Antiviral Drug Tilorone Is a Potent and Selective Inhibitor of Acetylcholinesterase.
The Antiviral Drug Tilorone Is a Potent and Selective Inhibitor of Acetylcholinesterase.
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DOI：
10.1021/acs.chemrestox.0c00466
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发表时间：
2021-05-17
影响因子：
4.1
通讯作者：
Ekins S
中科院分区：
文献类型：
--
作者：
Vignaux PA;Minerali E;Lane TR;Foil DH;Madrid PB;Puhl AC;Ekins S
乙酰胆碱酯酶（ACHE）是神经疾病中的重要药物靶标，例如阿尔茨海默氏病，路易斯的身体痴呆症和帕金森氏病痴呆症，以及其他疾病，在这项研究中，我们已经使用了较高的机器学习和鉴定依次的临时性。来自鳗鱼和人类ACHE抑制剂的化学数据的文献，以及丁酰胆碱酯酶抑制剂（Buche），并与其他机器学习方法进行了比较。鳗鱼和人类IC50分别为14.4 nm和64.4 nm，但并未抑制与密切相关的丁酰胆碱酯酶（Buche）IC50>50μm药品安全性（SafetysCreen44）和激酶选择性筛选（SelectScreen）显示tilorone（1μM）仅抑制了评估的44个毒理学靶蛋白中的ACHE，并且没有欣赏该研究的485个激酶，这可能会抑制485个激酶的抑制作用。
Acetylcholinesterase (AChE) is an important drug target in neurological disorders like Alzheimer’s Disease, Lewy Body dementia and Parkinson’s Disease dementia, as well as for other conditions like myasthenia gravis and anticholinergic poisoning. In this study we have used a combination of high throughput screening, machine learning and docking to identify new inhibitors of this enzyme. Bayesian machine learning models were generated with literature data from ChEMBL for eel and human AChE inhibitors, as well as butyrylcholinesterase inhibitors (BuChE), and compared with other machine learning methods. High throughput screens for the eel AChE inhibitor model identified several molecules including tilorone, an antiviral drug that is well-established outside of the United States, as a newly identified nanomolar AChE inhibitor. We have described how tilorone inhibits both eel and human AChE with IC50’s of 14.4 nM and 64.4 nM, respectively, but does not inhibit the closely related butyrylcholinesterase (BuChE) IC50 > 50 μM. We have docked tilorone into the human AChE crystal structure and shown that this selectivity is likely due to the reliance on a specific interaction with a hydrophobic residue in the peripheral anionic site of AChE that is absent in BuChE. We also conducted a pharmacological safety profile (SafetyScreen44) and kinase selectivity screen (SelectScreen) that showed tilorone (1 μM) only inhibited AChE out of 44 toxicology target proteins evaluated and did not appreciably inhibit any of the 485 kinases tested. This study suggests there may be a potential role for repurposing tilorone or its derivatives in conditions that benefit from AChE inhibition.
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影响因子：
3.7
作者：
Ekins, Sean;Gerlach, Jacob;Gerlach, Aaron
通讯作者：
Gerlach, Aaron
影响因子：
5.8
作者：
ELLMAN, GL;COURTNEY, KD;FEATHERSTONE, RM
通讯作者：
FEATHERSTONE, RM
DOI：
10.1080/14756366.2019.1571270
发表时间：
2019-01-01
影响因子：
5.6
作者：
de Souza, Gabriela Alves;da Silva, Soraia John;Kummerle, Arthur Eugen
通讯作者：
Kummerle, Arthur Eugen
DOI：
10.1080/14756366.2016.1220377
发表时间：
2016-01-01
影响因子：
5.6
作者：
De Vita, Daniela;Pandolfi, Fabiana;Scipione, Luigi
通讯作者：
Scipione, Luigi
影响因子：
41.2
作者：
Ekins, Sean;Puhl, Ana C.;Clark, Alex M.
通讯作者：
Clark, Alex M.