通过基于药效基团的筛选发现有效的、选择性的丁酰胆碱酯酶抑制剂。
Discovery of potent and selective butyrylcholinesterase inhibitors through the use of pharmacophore-based screening.
机构信息
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 S. Limestone, Lexington, KY 40536, United States.
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 S. Limestone, Lexington, KY 40536, United States.
出版信息
Bioorg Med Chem Lett. 2019 Dec 15;29(24):126754. doi: 10.1016/j.bmcl.2019.126754. Epub 2019 Oct 28.
Abstract
Cholinesterase inhibitors have long been used in the treatment of Alzheimer's Disease (AD) via the protection of acetylcholine levels. However, recent research has shown that the specific inhibition of butyrylcholinesterase (BChE) could better ameliorate symptoms within patients. In addition, it has recently been shown that selective inhibition of BChE can also significantly attenuate the toxicity and physiological effects of heroin. Currently, there are no specific and potent inhibitors of BChE approved for use in AD or heroin abuse. Through a combined use of in silico and in vitro screening, we have found three compounds with sub-50 nM IC values that specifically target BChE. These newly discovered BChE inhibitors can act as the lead scaffolds for future development of the desirably potent and selective BChE inhibitors.
摘要
胆碱酯酶抑制剂通过保护乙酰胆碱水平，长期以来一直被用于治疗阿尔茨海默病（AD）。然而，最近的研究表明，特定抑制丁酰胆碱酯酶（BChE）可以更好地改善患者的症状。此外，最近还表明，选择性抑制 BChE 还可以显著减轻海洛因的毒性和生理作用。目前，尚无专门针对 AD 或海洛因滥用的 BChE 特异性强效抑制剂获得批准。通过计算机模拟和体外筛选相结合的方法，我们发现了三种对 BChE 具有亚 50 nMIC 值的化合物，这些化合物具有特异性。这些新发现的 BChE 抑制剂可以作为未来开发理想强效和选择性 BChE 抑制剂的先导骨架。
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