Open Drug Discovery Center for Alzheimer's Disease

项目摘要/摘要 药物发现是一项本质上有风险的努力，已被证明在阿尔茨海默病(AD)中尤其如此。 项目开始时的风险可归类为“验证风险”(目标的调整将 在患者中有一个有利的结果)或“技术风险”(一种可耐受的调节分子的可能性 可以发现患者体内的靶点)。阿尔茨海默病药物研发中心(Open-AD) 该计划将创建一套互补的生物信息学、结构和药理学工具(高质量 化学探针)，以在开放的发现环境中评估各种AD假说。创建 在AD的细胞和动物模型中活跃的高质量化学探针与较少探索的靶点 可以降低发现治疗这种疾病的新药所固有的技术和验证风险。 Med Chem Core的科学家已经成功地开发并自由地与科学 社区一流的化学探测器，没有知识产权的负担。我们致力于探索 我们的首要假设是，开放的药物发现将加速AD药物的发展 通过对一系列未经测试的AD治疗假说进行稳健和独立的评估 利用所有工具中最有效的工具；高质量、细胞和体内活性的化学探针。 目标1.组合创建：Med Chem Core将与Bioinf和Struct Bio核心密切合作，以 选择一组与广告相关的新目标，每年有6个目标进入命中发现阶段。目标 将审查探测器发现的技术风险，并根据这一点和 疾病验证风险。 目标2.Hit发现：The Assay和Screen Core将在基于多样性的HTS上领先，实现Hit发现。 因此，医学化学核心将侧重于以知识为基础的补充方法，例如：虚拟 筛选，使用自定义库进行重点筛选，优化在 结构生物核心、结构导向配基设计和其他基本方法。 目标3.Hit to Probe：Med Chem Core将应用最先进的药物化学策略迭代 设计具有与中枢神经系统渗透一致的物理化学性质的类药物类似物。这些遗嘱 在一系列检测中进行评估，以解决靶向亲和力、选择性、细胞活性和体外ADME 属性。当化合物在这些检测中达到预期的活性时，它们将进入体内评估。 血浆/大脑PK和靶点交战。最终的探测器将被广泛地描述为支持他们的MOA 并用Assay和Screen Core评价其对AD模型的疗效。 Med Chem Core的总体目标是每年交付3个细胞探测器和1-2个体内探测器，而不是新的 涉及AD的目标，将向科学界免费提供。 ！1！

Project Summary/Abstract Drug discovery is an inherently risky endeavor and has proven to be especially so in Alzheimer’s disease (AD). Risk at project inception can be categorized as ‘validation risk’ (the likelihood that modulation of the target will have a favorable outcome in patients) or ‘technical risk’ (the likelihood that a tolerable molecule that modulates the target in patients can be discovered). The Open Drug Discovery Center for Alzheimer’s Disease (Open-AD) initiative will create a set of complementary bioinformatic, structural and pharmacologic tools (high-quality chemical probes) to evaluate a diverse set of AD hypotheses in an open discovery environment. Creation of high-quality chemical probes that are active in cellular and animal models of AD versus less explored targets can decrease the technical and validation risk inherent in discovery of new drugs for this disease. Scientists in the Med Chem Core have been successful in developing and sharing freely with the scientific community first-in-class chemical probes unburdened by intellectual property. We are committed to exploring our overarching hypothesis that open drug discovery will accelerate the development of AD medicines through robust and independent evaluation of a diverse set of untested AD therapeutic hypotheses utilizing the most impactful of all tools; a high-quality, cellular and in vivo active chemical probes. Aim 1. Portfolio creation: The Med Chem Core will work closely with the Bioinf and Struct Bio Cores to select a portfolio of novel AD related targets such that 6 targets enter the hit discovery phase each year. Targets will be vetted for the technical risk of probe discovery and prioritized for screening based upon this and the disease validation risk. Aim 2. Hit discovery: The Assay and Screen Core will take the lead on diversity-based HTS for hit discovery. The Med Chem Core will therefore focus on complementary, knowledge-based approaches, such as: virtual screening, focused screening using custom libraries, optimization of fragment-based hits discovered in the Struct Bio Core, structure-guided ligand design, and other rationale approaches. Aim 3. Hit to probe: The Med Chem Core will apply state-of-the-art medicinal chemistry strategies to iteratively design sets of drug-like analogues with physical-chemical properties consistent with CNS penetration. These will be assessed in a hierarchy of assays to address target affinity, selectivity, cellular activity, and in vitro ADME properties. As compounds achieve the desired activity in these assays, they will advance into in vivo assessment of plasma/brain PK and target engagement. Final probes will be extensively characterized to support their MOA and efficacy by the Assay and Screen Core in models of AD. The overall goal of the Med Chem Core is to deliver 3 cellular and 1-2 in vivo probes per year versus novel targets implicated in AD, which will be made freely available to the scientific community. ! 1!