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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.
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，报道的胆碱能假说表明神经递质乙酰胆碱(ACh)合成不足是导致这种疾病的原因.已经报道了加兰他敏结合的人乙酰胆碱酯酶（hAChE）的晶体结构；然而，加兰他敏对hAChE的抑制机制尚不清楚。已对加兰他敏结合的hAChE的晶体结构进行了回火元动力学（WTMtMD）模拟研究。所报道的ACh降解机制是通过从Glu334的羧基到Ser203的羟基的质子转移过程提出的，该过程攻击ACh降解为乙酸和胆碱。在加兰他敏的存在下，这种质子转移过程会降低，这是由于用WTMtD观察到的AChE峡谷内催化三联体的分离。已经进行了对接研究，以检查ACh与加兰他敏结合的hAChE的催化三联体的结合。对接结果表明，由于加兰他敏在酶的峡谷中的存在，ACh与催化三联体的途径被中断。
