Acetylcholinesterase (AChE), with a rigid structure and buried active site at the end of a deep narrow gorge, is interesting enough to solve the paradox between high catalytic activity and unavailability of the active site in treatment of Alzheimer's disease (AD). In this way, the blind docking process is performed on an ensemble of AChE structures created with molecular dynamics (MD) simulations to survey the whole space of AChE to find multiple access pathways to the active site and ranking them based on their affinity scores. Our results show that there are other allosteric binding sites in the protein structure whose inhibition, can affect protein function by disrupting the release of the Acetylcholine (AC) degradation products. In this study, inhibitory activities of Hybride14 and two natural compounds (Papaverine and Palmatine) were evaluated for all possible allosteric sites via docking method. The results confirmed the non-competitive inhibition mechanism. The best binding mode for these inhibitors and efficacy of hydrogen bonds and hydrophobic interactions on inhibitory activities of ligands were also disclosed. Furthermore, our studies provide significant molecular insight for AChE inhibition that could aid in the development of new drugs for AD's treatment.

乙酰胆碱酯酶 (AChE) 具有刚性结构和位于深窄峡谷末端的埋藏活性位点，足以解决高催化活性和活性位点在治疗阿尔茨海默病 (AD) 中不可用之间的悖论。通过这种方式，盲对接过程是在使用分子动力学 (MD) 模拟创建的 AChE 结构集合上执行的，以调查 AChE 的整个空间，以找到通往活性位点的多个通路，并根据它们的亲和力评分对它们进行排序。我们的结果表明，蛋白质结构中还有其他变构结合位点，其抑制作用可以通过破坏乙酰胆碱 (AC) 降解产物的释放来影响蛋白质功能。在这项研究中，通过对接方法对所有可能的变构位点评估了 Hybride14 和两种天然化合物（罂粟碱和棕榈碱）的抑制活性。结果证实了非竞争性抑制机制。还公开了这些抑制剂的最佳结合模式以及氢键和疏水相互作用对配体抑制活性的功效。此外，我们的研究为 AChE 抑制提供了重要的分子见解，有助于开发治疗 AD 的新药物。