Rational modification of known drug candidates to design more potent ones using computational methods has found application in drug design, development, and discovery. Herein, we integrate computational and theoretical methodologies to unveil rivastigmine derivatives as dual inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) for Alzheimer's disease (AD) management. The investigation entails pharmacokinetics screening, density functional theory (DFT) mechanistic study, molecular docking, and molecular dynamics (MD) simulation. We designed over 20 rivastigmine substituents, subject them to some analyses, and identified RL2 with an appreciable blood-brain barrier score and no permeability glycoprotein binding. The compound shows higher acylation energy and a favored binding affinity to the cholinesterase enzymes. RL2 interacts with the AChE and BuChE active sites showing values of −41.1/−39.5 kcal mol⁻¹ while rivastigmine binds with −32.7/−30.7 kcal mol⁻¹ for these enzymes. The study revealed RL2 (4-fluorophenyl rivastigmine) as a potential dual inhibitor for AChE and BuChE towards Alzheimer's disorder management.

中文翻译：

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卡巴拉汀衍生物作为双乙酰胆碱酯酶和丁酰胆碱酯酶抑制剂用于阿尔茨海默病治疗的定制模型

使用计算方法对已知候选药物进行合理修改以设计更有效的候选药物已在药物设计、开发和发现中得到应用。在这里，我们整合计算和理论方法，揭示卡巴拉汀衍生物作为乙酰胆碱酯酶 (AChE) 和丁酰胆碱酯酶 (BuChE) 的双重抑制剂，用于阿尔茨海默病 (AD) 管理。该研究需要药代动力学筛选、密度泛函理论 (DFT) 机理研究、分子对接和分子动力学 (MD) 模拟。我们设计了 20 多个卡巴拉汀取代基，对它们进行了一些分析，并确定了RL2具有可观的血脑屏障评分且无渗透性糖蛋白结合。该化合物显示出更高的酰化能和对胆碱酯酶有利的结合亲和力。RL2与 AChE 和 BuChE 活性位点相互作用，显示值为 -41.1/-39.5 kcal mol ^-1而卡巴拉汀与这些酶的-32.7/-30.7 kcal mol ^-1结合。该研究揭示了RL2（4-氟苯基卡巴拉汀）作为 AChE 和 BuChE 治疗阿尔茨海默病的潜在双重抑制剂。