A Computational Study of Phenothiazine Derivatives as Acetylcholinesterase Inhibitors Targeting Alzheimer's Disease.

Prema V, Prema A, Prema N
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Abstract

BACKGROUND Alzheimer's disease is a neurodegenerative disorder that affects learning, memory and behavioral turbulence in elderly patients. Acetylcholinesterase (AChE) inhibitors act as anti-Alzheimer's agents. Phenothiazine derivatives are considered momentous anti-Alzheimer's agents because of their AChE inhibitory activity. The elevated levels and increased expression of this protein have been associated with Alzheimer's disease. Coumarin-fused phenothiazines have emerged as significant anti-Alzheimer's agents due to their notable receptor inhibitory activity. OBJECTIVE Some unique phenothiazine analogs were designed, and computational studies were conducted to explore their inhibitory activity against the AChE enzyme (PDB id: 4EY7) by using the Schrodinger suite-2019-4. METHODS Docking studies were conducted by using the Glide module; binding free energies were calculated by means of the Prime MM-GBSA module, and Molecular dynamics (MD) simulation was performed by using the Desmond module of the Schrodinger suite. Glide scores were used to find out the binding affinity of the ligands with the target 4EY7. RESULTS The compounds exhibited enhanced hydrophobic interactions and formed hydrogen bonds, effectively impeding Acetylcholinesterase. The Glide scores for the compounds ranged from -13.4237 to -8.43439, surpassing the standard (Donepezil) with a score of -16.9898. Interestingly, a positive value was obtained for the MM-GBSA binding of the potent inhibitor. To gain insights into the dynamic behavior of the protein A8, molecular dynamics (MD) simulations were employed. CONCLUSION Based on the results, the study concludes that phenothiazine derivatives show promise as acetylcholinesterase inhibitors. Compounds with notable Glide scores are poised to exhibit significant anti-Alzheimer's activity, suggesting their potential therapeutic efficacy. Further in vitro and in vivo investigations are warranted to validate and explore the therapeutic potentials of these compounds.
针对阿尔茨海默病的乙酰胆碱酯酶抑制剂吩噻嗪衍生物的计算研究。
背景阿尔茨海默病是一种神经退行性疾病,会影响老年患者的学习、记忆和行为紊乱。乙酰胆碱酯酶(AChE)抑制剂可作为抗阿尔茨海默病的药物。吩噻嗪衍生物因其乙酰胆碱酯酶抑制活性而被认为是重要的抗阿尔茨海默氏症药物。这种蛋白质的水平升高和表达增加与阿尔茨海默病有关。目的设计了一些独特的吩噻嗪类似物,并利用 Schrodinger suite-2019-4 进行了计算研究,以探索它们对 AChE 酶(PDB id:4EY7)的抑制活性。方法利用 Glide 模块进行了对接研究;利用 Prime MM-GBSA 模块计算了结合自由能,并利用薛定谔套件的 Desmond 模块进行了分子动力学(MD)模拟。结果化合物表现出更强的疏水相互作用并形成氢键,有效地抑制了乙酰胆碱酯酶。这些化合物的 Glide 得分为 -13.4237 到 -8.43439,超过了标准化合物(多奈哌齐)的 -16.9898 分。有趣的是,强效抑制剂的 MM-GBSA 结合值为正值。为了深入了解蛋白质 A8 的动态行为,研究人员采用了分子动力学(MD)模拟。具有显著 Glide 评分的化合物有望表现出明显的抗阿尔茨海默氏症活性,这表明它们具有潜在的治疗功效。有必要进一步开展体外和体内研究,以验证和探索这些化合物的治疗潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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