Tounge Brett A, Reynolds Charles H
Johnson & Johnson Pharmaceutical Research and Development, L.L.C., P.O. Box 776, Welsh and McKean Roads, Spring House, Pennsylvania 19477-0776, USA.
J Med Chem. 2003 May 22;46(11):2074-82. doi: 10.1021/jm020513b.
It has been shown that the rate-limiting step in the production of beta-amyloid peptide (Abeta) is the proteolytric cleavage of the membrane-bound beta-amyloid precursor protein (APP) by beta-secretase (BACE). Since the accumulation of Abeta has been implicated as one of the key events in the progression of Alzheimer's disease, BACE has become an important therapeutic target. Recently, two crystal structures of BACE cocrystallized with the inhibitors OM99-2 and OM00-3 were published by Tang and co-workers. In addition, the Ghosh group has published binding data on a series of inhibitors based on their initial lead, OM99-2. Using this set as a basis, we have developed a model for the binding affinity of these ligands to BACE using the linear interaction energy method. The best binding affinity model for the full set of ligands had a RMSD of 1.10 kcal/mol. The best model excluding the two charged ligands had a RMSD of 0.87 kcal/mol.
已经表明，β-淀粉样肽（Aβ）产生过程中的限速步骤是β-分泌酶（BACE）对膜结合的β-淀粉样前体蛋白（APP）进行蛋白水解切割。由于Aβ的积累被认为是阿尔茨海默病进展中的关键事件之一，BACE已成为一个重要的治疗靶点。最近，Tang及其同事发表了BACE与抑制剂OM99-2和OM00-3共结晶的两个晶体结构。此外，Ghosh团队发表了基于其最初先导化合物OM99-2的一系列抑制剂的结合数据。以此为基础，我们使用线性相互作用能方法开发了这些配体与BACE结合亲和力的模型。全套配体的最佳结合亲和力模型的均方根偏差为1.10千卡/摩尔。排除两个带电荷配体后的最佳模型的均方根偏差为0.87千卡/摩尔。
