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Abstract：
Acetylcholinesterase (AChE) is one of the main drug targets for treating Alzheimer\'s disease. This current study relies on multiple molecular modeling approaches to develop new potent inhibitors of AChE. We explored a 2D QSAR study using the statistical method of multiple linear regression based on a set of substituted 5-phenyl-1,3,4-oxadiazole and N-benzylpiperidine analogs, which were recently synthesized and proved their inhibitory activities against acetylcholinesterase (AChE). The molecular descriptors, polar surface area, dipole moment, and molecular weight are the key structural properties governing AChE inhibition activity. The MLR model was selected based on its statistical parameters: R2 = 0.701, R2test = 0.76, Q2CV = 0.638, and RMSE = 0.336, demonstrating its predictive reliability. Randomization tests, VIF tests, and applicability domain tests were adopted to verify the model\'s robustness. As a result, 11 new molecules were designed with higher anti-Alzheimer\'s activities than the model molecule. We demonstrated their improved pharmacokinetic properties through an in silico ADMET study. A molecular docking study was conducted to explore their AChE inhibition mechanisms and binding affinities in the active site. The binding scores of compounds M1, M2, and M6 were (-12.6 kcal/mol), (-13 kcal/mol), and (-12.4 kcal/mol), respectively, which are higher than the standard inhibitor Donepezil with a binding score of (-10.8 kcal/mol). Molecular dynamics simulations over 100 ns were used to validate the molecular docking results, indicating that compounds M1 and M2 remain stable in the active site, confirming their potential as promising anti-AChE inhibitors.
摘要：
乙酰胆碱酯酶(AChE)是治疗阿尔茨海默病的主要药物靶点之一。目前的这项研究依赖于多种分子建模方法来开发新的有效的AChE抑制剂。我们基于一组取代的5-苯基-1,3,4-恶二唑和N-苄基哌啶类似物，使用多元线性回归的统计方法探索了2DQSAR研究，它们是最近合成的，并证明了它们对乙酰胆碱酯酶（AChE）的抑制活性。分子描述符，极性表面积，偶极矩,和分子量是控制AChE抑制活性的关键结构特性。根据统计参数选择MLR模型：R2=0.701，R2检验=0.76，Q2CV=0.638，RMSE=0.336，证明了其预测可靠性。随机化试验,VIF测试,采用适用性领域试验验证了模型的稳健性。因此,设计了11种新分子，具有比模型分子更高的抗阿尔茨海默病活性。我们通过计算机模拟ADMET研究证明了它们改善的药代动力学特性。进行了分子对接研究以探索它们的AChE抑制机制和活性位点中的结合亲和力。化合物M1、M2和M6的结合评分为(-12.6kcal/mol),（-13千卡/摩尔），和（-12.4千卡/摩尔），分别,其高于标准抑制剂多奈哌齐,结合评分为(-10.8kcal/mol)。使用超过100ns的分子动力学模拟来验证分子对接结果，表明化合物M1和M2在活性位点保持稳定，证实了它们作为有前途的抗AChE抑制剂的潜力。
