背景:阿尔茨海默病,类似于心脏的冠状动脉疾病,是一种由神经细胞损伤引起的进行性脑部疾病。
方法:本研究利用计算方法探索了14种抗乙酰胆碱酯酶(AChE)衍生物(1-14)作为潜在治疗方法。通过仔细检查它们与11种必需靶蛋白(AChE,Aβ,BChE,GSK-3β,MAOB,PDE-9,朊病毒,PSEN-1,sEH,Tau,和TDP-43),并将其与已建立的药物如多奈哌齐进行比较,加兰他敏,美金刚,还有利伐斯的明,配体14显现出来。在分子动力学模拟中,与关键1QTI蛋白具有最强键并超过药物相似性标准的蛋白质在不同温度(300-320K)下也在酶的口袋中表现出显著的稳定性。此外,我们利用密度泛函理论(DFT)来计算偶极矩和分子轨道性质,包括评估AChE衍生物的热力学稳定性。
结果:这一发现表明,潜在的治疗相互作用进一步支持理论和未来的体外和体内研究。
结论:配体14因此成为对抗阿尔茨海默病的有希望的候选者。
BACKGROUND: Alzheimer\'s disease, akin to coronary artery disease of the heart, is a progressive brain disorder driven by nerve cell damage.
METHODS: This study utilized computational methods to explore 14 anti-acetylcholinesterase (AChE) derivatives (1 ̶ 14) as potential treatments. By scrutinizing their interactions with 11 essential target proteins (AChE, Aβ, BChE, GSK-3β, MAO B, PDE-9, Prion, PSEN-1, sEH, Tau, and TDP-43) and comparing them with established drugs such as donepezil, galantamine, memantine, and rivastigmine, ligand 14 emerged as notable. During molecular dynamics simulations, the protein boasting the strongest bond with the critical 1QTI protein and exceeding drug-likeness criteria also exhibited remarkable stability within the enzyme\'s pocket across diverse temperatures (300 ̶ 320 K). In addition, we utilized density functional theory (DFT) to compute dipole moments and molecular orbital properties, including assessing the thermodynamic stability of AChE derivatives.
RESULTS: This finding suggests a welldefined, potentially therapeutic interaction further supported by theoretical and future in vitro and in vivo investigations.
CONCLUSIONS: Ligand 14 thus emerges as a promising candidate in the fight against Alzheimer\'s disease.