Kryger G, Silman I, Sussman J L
Department of Structural Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
Structure. 1999 Mar 15;7(3):297-307. doi: 10.1016/s0969-2126(99)80040-9.
Several cholinesterase inhibitors are either being utilized for symptomatic treatment of Alzheimer's disease or are in advanced clinical trials. E2020, marketed as Aricept, is a member of a large family of N-benzylpiperidine-based acetylcholinesterase (AChE) inhibitors developed, synthesized and evaluated by the Eisai Company in Japan. These inhibitors were designed on the basis of QSAR studies, prior to elucidation of the three-dimensional structure of Torpedo californica AChE (TcAChE). It significantly enhances performance in animal models of cholinergic hypofunction and has a high affinity for AChE, binding to both electric eel and mouse AChE in the nanomolar range.
Our experimental structure of the E2020-TcAChE complex pinpoints specific interactions responsible for the high affinity and selectivity demonstrated previously. It shows that E2020 has a unique orientation along the active-site gorge, extending from the anionic subsite of the active site, at the bottom, to the peripheral anionic site, at the top, via aromatic stacking interactions with conserved aromatic acid residues. E2020 does not, however, interact directly with either the catalytic triad or the 'oxyanion hole', but only indirectly via solvent molecules.
Our study shows, a posteriori, that the design of E2020 took advantage of several important features of the active-site gorge of AChE to produce a drug with both high affinity for AChE and a high degree of selectivity for AChE versus butyrylcholinesterase (BChE). It also delineates voids within the gorge that are not occupied by E2020 and could provide sites for potential modification of E2020 to produce drugs with improved pharmacological profiles.
几种胆碱酯酶抑制剂已用于阿尔茨海默病的症状治疗或正处于晚期临床试验阶段。作为安理申上市的E2020，是日本卫材公司研发、合成和评估的基于N-苄基哌啶的乙酰胆碱酯酶（AChE）抑制剂大家族中的一员。这些抑制剂是在阐明加州电鳐AChE（TcAChE）三维结构之前，根据定量构效关系研究设计的。它能显著提高胆碱能功能减退动物模型的表现，对AChE具有高亲和力，在纳摩尔范围内与电鳗和小鼠AChE结合。
我们得到的E2020-TcAChE复合物的实验结构确定了先前证明的负责高亲和力和选择性的特定相互作用。结果表明，E2020沿着活性位点峡谷具有独特的取向，从底部活性位点的阴离子亚位点延伸到顶部的外周阴离子位点，通过与保守芳香酸残基的芳香堆积相互作用实现。然而，E2020并不直接与催化三联体或“氧阴离子洞”相互作用，而是仅通过溶剂分子间接相互作用。
我们的研究事后表明，E2020的设计利用了AChE活性位点峡谷的几个重要特征，从而产生了一种对AChE具有高亲和力且对AChE相对于丁酰胆碱酯酶（BChE）具有高度选择性的药物。它还描绘了峡谷内未被E2020占据的空隙，这些空隙可为E2020的潜在修饰提供位点，以生产具有改善药理特性的药物。
