Drug-likeness parameters according to Lipinski.

Alzheimer’s disease (AD) causes a progressive decline in memory, along with impairments in other cognitive abilities. The main pharmacological target for Alzheimer’s disease (AD) treatment is acetylcholinesterase (AChE), a biochemical enzyme belonging to the cholinesterase (ChE) family. In the search for novel hit compoundswith potential as future Alzheimer's therapies, a series of carbamates derivatives were designed and evaluated using computational approaches including QSAR modeling, molecular docking, ADMET profiling, and molecular dynamics simulations. The following study focused on the development of a QSAR model with satisfactory statistical properties. ADMET analysis on the designed ligands, demonstrated good pharmacokinetic properties. Molecular docking identified M6 as a promising AChE binder with a docking score of -11.200 kcal/mol, while the Donepezil control returned a docking score of -10.800 kcal/mol. The validity of the docked complex was confirmed using molecular dynamics simulations, where the trajectory plots of M6 were found to be stable and consistent over 100 ns intervals. The enclosed study highlights M6 as a novel chemical starting point (CSP) (i.e., hit compound) targeting AChE as a potential therapeutic strategy against AD.

阿尔茨海默病（Alzheimer’s disease, AD）会引发记忆力进行性衰退，并伴随其他认知能力受损。阿尔茨海默病治疗的主要药理学靶点为乙酰胆碱酯酶（acetylcholinesterase, AChE），这是一类隶属于胆碱酯酶（cholinesterase, ChE）家族的生化酶。在筛选可作为未来阿尔茨海默病治疗候选的新型命中化合物过程中，研究人员通过定量构效关系（Quantitative Structure-Activity Relationship, QSAR）建模、分子对接（molecular docking）、ADMET分析及分子动力学模拟（molecular dynamics simulations）等计算方法，设计并评估了一系列氨基甲酸酯类衍生物。本研究聚焦于构建具有良好统计性能的QSAR模型。对所设计配体的ADMET分析结果显示其具备优良的药代动力学特性。分子对接结果表明，化合物M6是极具潜力的AChE结合配体，对接得分为-11.200 kcal/mol，而作为对照的多奈哌齐（Donepezil）对接得分为-10.800 kcal/mol。通过分子动力学模拟验证了该对接复合物的有效性：M6的模拟轨迹在100 ns的模拟时长内保持稳定且一致性良好。本项研究证实M6可作为靶向AChE的新型化学起始点（chemical starting point, CSP，即命中化合物），为阿尔茨海默病的潜在治疗策略提供了新的研发起点。