Synthesis, kinetic evaluation and molecular docking studies of donepezil-based acetylcholinesterase inhibitors
Synthesis, kinetic evaluation and molecular docking studies of donepezil-based acetylcholinesterase inhibitors
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DOI：
10.1016/j.molstruc.2021.131425
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发表时间：
2021-09-10
影响因子：
3.8
通讯作者：
Pecic, Stevan
中科院分区：
文献类型：
--
作者：
Makarian, Makar;Gonzalez, Michael;Pecic, Stevan
为了开发治疗阿尔茨海默病的新治疗药物，我们设计了一系列基于多奈哌齐的类似物，采用环保途径合成，并对其对电鳗乙酰胆碱酯酶（AChE）的抑制活性进行了生物学评估。体外研究表明，多奈哌齐的苯基部分可以成功地被吡啶环取代，从而产生同样有效的电鳗乙酰胆碱酯酶抑制剂。对最有效的抑制剂的进一步动力学评估显示出双重结合（混合抑制）模式，类似于多奈哌齐。分子模型研究表明，与多奈哌齐相比，几个额外的残基可能参与该抑制剂在人乙酰胆碱酯酶活性位点的结合。 (C) 2021 作者。由 Elsevier B.V. 出版
In an effort to develop new therapeutic agents to treat Alzheimer's disease, a series of donepezil-based analogs were designed, synthesized using an environmentally friendly route, and biologically evaluated for their inhibitory activity against electric eel acetylcholinesterase (AChE) enzyme. In vitro studies revealed that the phenyl moiety of donepezil can be successfully replaced with a pyridine ring leading to equally potent inhibitors of electric eel AChE. Further kinetic evaluations of the most potent inhibitor showed a dual-binding (mixed inhibition) mode, similar to donepezil. Molecular modeling studies suggest that several additional residues could be involved in the binding of this inhibitor in the human AChE enzyme active site compared to donepezil. (C) 2021 The Author(s). Published by Elsevier B.V.