The rationale for E2020 as a potent acetylcholinesterase inhibitor
The rationale for E2020 as a potent acetylcholinesterase inhibitor
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DOI：
10.1016/0968-0896(96)00137-x
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发表时间：
1996-09-01
影响因子：
3.5
通讯作者：
Hopfinger, AJ
中科院分区：
文献类型：
--
作者：
Kawakami, Y;Inoue, A;Hopfinger, AJ
III期候选药物，E2020，开发用于治疗阿尔茨海默病，并可能其他demenitas，及其类似物已成为广泛的分子药理学和结构研究的焦点。建立了E2020作为脑中乙酰胆碱酯酶（AChE）抑制剂的效力和选择性。结合分子建模和QSAR研究已被用于整个演变的乙酰胆碱酯酶抑制剂计划导致苄基哌啶系列，并最终，E2020。QSAR研究已经确定了优化抑制活性的要求，作为E2020类抑制剂中茚酮和苄基环上取代基选择的函数。E2020异构体的X射线晶体结构研究和E2020及其类似物的分子形状分析（MSA）的组合导致了这些AChE抑制剂的假定活性构象和分子形状。活性分子形状对应于两种E2020异构体之间的高度形状相似性，这反过来又与观察到的这两种化合物的高抑制效力一致。当E2020和一些类似物的晶体结构的乙酰胆碱酯酶，它变得可用时，进行了分子间对接研究。涉及E2020类似物的对接模拟表明，这些抑制剂不结合在乙酰胆碱，乙酰胆碱，活性位点，而是在最窄的位置的长通道导致的活性位点。分子间结合的几何形状是一致的，与假定的活性构象来自结构活性（受体几何形状独立）的信息。版权所有（C）1996 Elsevier Science Ltd
The phase III drug-candidate, E2020, developed for treatment of Alzheimer's disease, and possibly other demenitas, and its analogues have been the focus of extensive molecular pharmacological and structural studies. The potency and selectivity of E2020 as an inhibitor of acetylcholinesterase, AChE, in the brain is established. A combination of molecular modeling and QSAR studies have been used throughout the evolution of the AChE inhibitor program leading to the benzylpiperidine series, and, ultimately, E2020. QSAR studies have identified requirements to optimize inhibition activity as a function of substituent choice on both the indanone and benzyl rings in the E2020 class of inhibitors. A combination of X-ray crystal structure studies of E2020 isomers and the molecular shape analysis, MSA, of E2020 and its analogues has led to a postulated active conformation, and molecular shape, for these AChE inhibitors. The active molecular shape corresponds to a high degree of shape similarity between the two E2020 isomers which, in turn, is consistent with the observed high inhibition potencies of both of these compounds. Intermolecular docking studies were carried out for E2020 and some analogues with the crystal structure of AChE when it became available. The docking simulations involving E2020 analogues suggest these inhibitors do not bind at the acetylcholine, ACh, active site, but rather at the most narrow location of the long channel leading to the active site. Intermolecular binding geometries are consistent with the postulated active conformations derived from structure-activity (receptor geometry independent) information. Copyright (C) 1996 Elsevier Science Ltd