Acetylcholinesterase (AChE) has emerged as an important drug target for the treatment of neurodegenerative disorders such as Alzheimer's disease (AD). Recent experimental studies indicate that certain antidiabetic drugs can be repurposed as potent AChE inhibitors. Enzymatic kinetic assays suggest that the antidiabetic drug chlorpropamide (CPM) acts as a noncompetitive inhibitor, but the mechanism of action and the binding site(s) of interaction with AChE are not known. In this work, we have carried out molecular dynamics (MD) simulations to discover a new allosteric site in addition to the known peripheral anionic site (PAS) as a potential binding site of this noncompetitive inhibitor. We show that the conformational ensemble of the catalytic triad, particularly the HIS447, undergoes a significant population shift on ligand binding that is responsible for deactivation of the enzyme. We also elucidate the pathway of the allosteric signaling in terms of locally correlated domains of the inter-residue interaction network. Thus, our work identifies a new allosteric site for AChE inhibition and eludiates the underlying mechanistic principles. These results would be useful for the rational design of new noncompetitive inhibitors for AChE.

中文翻译：

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阐明抗糖尿病药物氯磺丙脲非竞争性抑制乙酰胆碱酯酶的分子机制：鉴定新的变构位点


乙酰胆碱酯酶 （AChE） 已成为治疗阿尔茨海默病 （AD） 等神经退行性疾病的重要药物靶点。最近的实验研究表明，某些抗糖尿病药物可以重新用作有效的 AChE 抑制剂。酶动力学测定表明，抗糖尿病药物氯丙脲 （CPM） 是一种非竞争性抑制剂，但作用机制和与 AChE 相互作用的结合位点尚不清楚。在这项工作中，我们进行了分子动力学 （MD） 模拟，除了已知的外周阴离子位点 （PAS） 之外，还发现了一个新的变构位点作为这种非竞争性抑制剂的潜在结合位点。我们表明，催化三联体的构象集合，特别是 HIS447，在导致酶失活的配体结合上经历了显着的种群转移。我们还根据残基间相互作用网络的局部相关结构域阐明了变构信号转导的途径。因此，我们的工作确定了 AChE 抑制的新变构位点，并阐明了潜在的机制原理。这些结果将有助于 AChE 的新型非竞争性抑制剂的合理设计。