Tools for AD Research: Design of BACE2 Ligands

AD 研究工具：BACE2 配体的设计

• 批准号: 7021009
• 负责人: Pavel A Petukhov
• 金额: $ 21.14万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7021009
• 关键词: Alzheimer' s disease; amyloid proteins; aspartic endopeptidases; bioassay; brain disorder chemotherapy; cell free system; chemical binding; chemical kinetics; chemical registry /resource; combinatorial chemistry; computational biology; computer simulation; cytotoxicity; drug discovery /isolation; enzyme inhibitors; isozymes; ligands; nanotechnology; small molecule

DESCRIPTION (provided by applicant): This R21 exploratory proposal uses an integrated, target-oriented approach in the rational development of BACE2 inhibitors - chemical tools that can be used to explore the basic biology of BACE2 and improve the selectivity of presently discovered active BACE1 inhibitors that are currently being developed as medications for Alzheimer's disease. There exists a broad consensus in the AD research community that the key to successful treatment of AD lies in the specific inhibition of BACE1. BACE1 is crucial for release of the amyloidogenic fragments that later form the extracellular neuritic amyloid plaques - one of factors in the pathogenesis of AD. Most of the known BACE1 inhibitors are relatively non-selective and target other aspartic proteases including the highly homologous BACE2. It has been shown that BACE2 may serve as an alternative alpha-secretase, another crucial enzyme that plays an important role in degradation of the amyloid precursor protein (APR), inhibition of which is highly undesirable. To better understand the role of BACE2 in human physiology and APP processing, we believe that selective inhibitors of this enzyme are needed as research tools. We hypothesize that it should be possible to design and synthesize inhibitors for BACE2 using an integrated multidisciplinary approach based on the combination of the computer-aided drug design, medicinal chemistry, and biology. Those compounds demonstrating BACE2 activity in the low nanomolar range will be screened at the whole cell level for their ability to alter APP processing. This iterative process is expected to yield several low nanomolar, lead- or drug-like selective inhibitors of BACE2. To achieve this goal, our specific aims are as follow: (1) Identify lead- and drug-like low molecular weight selective inhibitors of BACE2 using computer-aided drug design including de novo/rational drug design, virtual focused combinatorial library (vFCL) generation, and in silico screening of vFCL. To synthesize the best candidates from the de novo/rational design and vFCL approaches; (2) Assay candidate ligands for their inhibition of BACE1 and BACE2 in isolated enzyme assays. Potent, selective BACE2 inhibitors will be used for further optimization of ligand activity and selectivity through iterative molecular modeling, chemical synthesis, and biological tests; (3) For the best ligands, explore their effects on APP processing in cell-based assays. Prioritize inhibitors on the basis of activity, cytotoxicity, and resultant selectivity indices.

描述（由申请人提供）：该 R21 探索性提案在 BACE2 抑制剂的合理开发中采用了综合的、以目标为导向的方法——化学工具可用于探索 BACE2 的基础生物学并提高目前发现的活性 BACE1 抑制剂的选择性目前正在开发治疗阿尔茨海默病的药物。 AD研究界已达成广泛共识，成功治疗AD的关键在于特异性抑制BACE1。 BACE1 对于淀粉样蛋白生成片段的释放至关重要，这些片段随后形成细胞外神经炎淀粉样斑块，这是 AD 发病机制的因素之一。大多数已知的 BACE1 抑制剂相对无选择性，并且靶向其他天冬氨酸蛋白酶，包括高度同源的 BACE2。研究表明，BACE2 可以作为替代的 α 分泌酶，这是另一种关键酶，在淀粉样前体蛋白 (APR) 的降解中发挥重要作用，抑制该酶是非常不受欢迎的。为了更好地了解 BACE2 在人体生理学和 APP 加工中的作用，我们认为需要该酶的选择性抑制剂作为研究工具。我们假设应该可以使用基于计算机辅助药物设计、药物化学和生物学相结合的综合多学科方法来设计和合成 BACE2 抑制剂。那些在低纳摩尔范围内表现出 BACE2 活性的化合物将在全细胞水平上筛选其改变 APP 加工的能力。这一迭代过程预计会产生几种低纳摩尔、先导或药物样的 BACE2 选择性抑制剂。为了实现这一目标，我们的具体目标如下：（1）利用计算机辅助药物设计（包括从头/理性药物设计、虚拟聚焦组合库（vFCL））识别BACE2的先导和类药低分子量选择性抑制剂vFCL 的生成和计算机筛选。通过从头/理性设计和 vFCL 方法综合最佳候选方案； (2) 在分离酶测定中测定候选配体对 BACE1 和 BACE2 的抑制作用。有效的选择性 BACE2 抑制剂将用于通过迭代分子建模、化学合成和生物测试进一步优化配体活性和选择性； (3) 对于最佳配体，探索它们对基于细胞的测定中 APP 处理的影响。根据活性、细胞毒性和由此产生的选择性指数对抑制剂进行优先排序。