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 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.

中文翻译：

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抗病毒药物 Tilorone 是一种有效的选择性乙酰胆碱酯酶抑制剂

乙酰胆碱酯酶 (AChE) 是治疗阿尔茨海默病、路易体痴呆和帕金森病痴呆等神经系统疾病以及重症肌无力和抗胆碱能中毒等其他疾病的重要药物靶点。在这项研究中，我们结合使用高通量筛选、机器学习和对接来识别这种酶的新抑制剂。贝叶斯机器学习模型是使用来自 ChEMBL 的鳗鱼和人类 AChE 抑制剂以及丁酰胆碱酯酶抑制剂 (BuChE) 的文献数据生成的，并与其他机器学习方法进行比较。鳗鱼 AChE 抑制剂模型的高通量筛选确定了几种分子，包括 tilorone，一种在美国以外广为人知的抗病毒药物，作为新发现的纳摩尔 AChE 抑制剂。₅₀分别为 14.4 nM 和 64.4 nM，但不抑制密切相关的 BuChE IC ₅₀ > 50 μM。我们已将 tilorone 与人类 AChE 晶体结构对接，并表明这种选择性可能是由于依赖于与 AChE 外周阴离子位点中的疏水残基的特定相互作用，而 BuChE 中不存在该疏水残基。我们还进行了药理学安全性概况 (SafetyScreen44) 和激酶选择性筛选 (SelectScreen)，结果显示 tilorone (1 μM) 仅抑制评估的 44 种毒理学靶蛋白中的 AChE，并且没有明显抑制所测试的 485 种激酶中的任何一种。该研究表明，在受益于 AChE 抑制的条件下，重新利用 tilorone 或其衍生物可能具有潜在作用。