Dickerson Tobin J, Beuscher Albert E, Rogers Claude J, Hixon Mark S, Yamamoto Noboru, Xu Yang, Olson Arthur J, Janda Kim D
Department of Chemistry, Molecular Biology and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Biochemistry. 2005 Nov 15;44(45):14845-53. doi: 10.1021/bi051613x.
The formation of beta-amyloid plaques in the brain is a key neurodegenerative event in Alzheimer's disease. Small molecules capable of binding to the peripheral anionic site of acetylcholinesterase (AChE) have been shown to inhibit the AChE-induced aggregation of the beta-amyloid peptide. Using the combination of a computational docking model and experimental screening, five compounds that completely blocked the amyloidogenic effect of AChE were rapidly identified from an approximately 200-member library of compounds designed to disrupt protein-protein interactions. Critical to this docking model was the inclusion of two explicit water molecules that are tightly bound to the enzyme. Interestingly, none of the tested compounds inhibited the related enzyme butyrylcholinesterase (BuChE) up to their aqueous solubility limits. These compounds are among the most potent inhibitors of amyloid beta-peptide aggregation and are equivalent only to propidium, a well-characterized AChE peripheral anionic site binder and aggregation inhibitor.
大脑中β-淀粉样蛋白斑块的形成是阿尔茨海默病关键的神经退行性事件。已证明能够结合乙酰胆碱酯酶（AChE）外周阴离子位点的小分子可抑制AChE诱导的β-淀粉样肽聚集。通过计算对接模型与实验筛选相结合，从一个旨在破坏蛋白质-蛋白质相互作用的约200种化合物库中快速鉴定出5种完全阻断AChE淀粉样生成作用的化合物。该对接模型的关键在于纳入了两个与酶紧密结合的明确水分子。有趣的是，在所测试的化合物中，没有一种在达到其水溶性极限之前能抑制相关酶丁酰胆碱酯酶（BuChE）。这些化合物是最有效的淀粉样β肽聚集抑制剂之一，仅等同于碘化丙啶，一种特征明确的AChE外周阴离子位点结合剂和聚集抑制剂。
