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）：此R21探索性提案在BACE2抑制剂的合理发展中使用了一种集成的，面向目标的方法 - 可用于探索BACE2的基本生物学的化学工具，并提高目前发现的活性BACE1抑制剂的选择性，这些抑制剂目前正在为Alzheimer疾病而开发为Alzheimer疾病的药物。广告研究界存在广泛的共识，即成功治疗AD的关键在于对Bace1的特定抑制。 BACE1对于释放淀粉样蛋白生成片段至关重要，淀粉样蛋白生成片段后来形成了细胞外神经淀粉样蛋白斑 - AD发病机理中的一个因素之一。大多数已知的BACE1抑制剂是相对非选择性的，并且靶向其他天冬氨酸，包括高度同源的Bace2。已经表明，BACE2可以用作替代性α-分泌酶，这是另一种至关重要的酶，在淀粉样蛋白前体蛋白（APR）降解中起重要作用，其抑制是高度不良的。为了更好地了解BACE2在人类生理和应用程序加工中的作用，我们认为需要选择该酶作为研究工具的选择性抑制剂。我们假设应该根据计算机辅助药物设计，药物化学和生物学的组合，使用综合的多学科方法来设计和合成BACE2的抑制剂。这些化合物表明在低纳摩尔范围内的BACE2活性，将在整个细胞水平上筛选其改变应用程序处理的能力。这种迭代过程有望产生BACE2的几种低纳摩尔，铅或药物样的选择性抑制剂。为了实现这一目标，我们的具体目标如下：（1）使用计算机辅助药物设计，包括从头/合理的药物设计，虚拟聚焦组合图书馆（VFCL）生成，以及在VFCL的硅筛选中，确定BACE2的铅和药物样低分子量选择性抑制剂。从头/理性设计和VFCL方法中综合最佳候选人； （2）测定候选配体在分离的酶测定中抑制BACE1和BACE2。有效的选择性BACE2抑制剂将用于通过迭代分子建模，化学合成和生物学测试进一步优化配体活性和选择性。 （3）对于最佳配体，请探索它们对基于细胞测定的应用程序处理的影响。根据活性，细胞毒性和结果选择性指数确定抑制剂的优先级。