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Revealing the cholinergic inhibition mechanism of Alzheimer’s by galantamine: a metadynamics simulation study
Journal of Biomolecular Structure and Dynamics ( IF 2.7 ) Pub Date : 2020-12-31 , DOI: 10.1080/07391102.2020.1867644
Shibaji Ghosh 1, 2 , Kalyanashis Jana 1, 2 , Padmaja D Wakchaure 1, 2 , Bishwajit Ganguly 1, 2
Affiliation  

Abstract

Galantamine is one of the approved drugs based on the cholinergic hypothesis for the symptomatic treatment of mild to moderate Alzheimer’s disease (AD). The etiology of AD is not fully known; however, the reported cholinergic hypothesis suggests the inadequate synthesis of the neurotransmitter acetylcholine (ACh) is responsible for this disease. The crystal structure of galantamine bound human acetylcholinesterase (hAChE) has been reported; however, the inhibition mechanism of hAChE by galantamine is not well understood. A Well-tempered metadynamics (WTMtD) simulation study has been performed with the crystal structure of galantamine bound hAChE. The reported mechanism for the degradation of ACh is suggested through a proton transfer process from a carboxylic group of Glu334 to the hydroxyl group of Ser203, which attacks ACh for the degradation to acetic acid and choline. Such proton transfer process is lowered in the presence of galantamine due to the separation of catalytic triad inside the gorge of AChE as observed with WTMtD. A docking study has been performed to examine the ACh's binding with the catalytic triad of galantamine bound hAChE. The docking results reveal that the approach of ACh to the catalytic triad is interrupted due to the galantamine's presence in the gorge of the enzyme.



中文翻译:

加兰他敏揭示阿尔茨海默氏症的胆碱能抑制机制:元动力学模拟研究

摘要

加兰他敏是基于胆碱能假说的批准药物之一,用于轻度至中度阿尔茨海默病 (AD) 的对症治疗。AD的病因尚不完全清楚;然而,报告的胆碱能假说表明神经递质乙酰胆碱 (ACh) 的合成不足是导致这种疾病的原因。加兰他敏结合人乙酰胆碱酯酶 ( h AChE) 的晶体结构已有报道;然而,加兰他敏对h AChE的抑制机制尚不清楚。已经对加兰他敏结合h的晶体结构进行了良好回火的元动力学 (WTMtD) 模拟研究疼痛。所报道的乙酰胆碱降解机制是通过质子转移过程从 Glu334 的羧基转移到 Ser2O3 的羟基的,它攻击乙酰胆碱以降解为乙酸和胆碱。由于如 WTMtD 观察到的 AChE 峡谷内催化三联体的分离,这种质子转移过程在加兰他敏存在下降低。已进行对接研究以检查 ACh 与加兰他敏催化三联体结合的h AChE 的结合。对接结果表明,由于加兰他敏存在于酶的峡谷中,ACh 与催化三联体的接近被中断。

更新日期:2020-12-31
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