Target enablement

目标实现

• 批准号: 10513872
• 负责人: John Damon Chodera
• 金额: $ 654.58万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-16 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10513872
• 关键词: Structure

The success of the Center's drug discovery programs relies on being experimentally fully enabled to support compound development. In the Target Enablement project, we will develop and validate the experimental procedures by producing "Target Enabling Packages" (TEPs). These comprise a set of experimental protocols and outputs that generate the rapid, reliable, full-spectrum readouts that underpin the acceleration of the designmake- test-analyze (DMTA) cycles. TEPs are highly effective enablers of medicinal chemistry on targets and targeting modalities where they can be achieved; nevertheless, frequently they remain incomplete, since they require great effort to assemble from literature and/or trial-and-error experiments; and determined medicinal chemists might manage to progress compound series anyway. However, this conceals the real and opportunity costs of doing so, which includes the synthesis of unnecessary compounds, pursuit of dead-end hypotheses, and poor models of the data. In the Target Enablement project, we propose to generate next generation TEPs that include the reagents and protocols for generating biochemically-behaved, well-crystallizing protein, 3D interaction maps of the binding site(s) from a crystal-based fragment screen, biochemical and biophysical assays and persuasive hit compounds, displaying consistent low micromolar affinity, activity and binding pose, rationalizable across a set of analogues. We will deliver TEPs that are rigorous, effective, and reproducible, by (a) contracting in the established, systematic workflow developed since 2015 at the University of Oxford, and (b) implementing and hardening of recent innovations and new technologies, including methods developed in the wake of the COVID Moonshot and other pandemic-related work. The specific goal of Project 2 is thus to generate next generation TEPs for 10 targets, to drive rapid hit-to-lead progression in Project 3 and thence validation of the antiviral hypothesis by virology and chemical biology. The goal is spread over 4 Aims, with Aim 1 establishing biochemical and crystal structure tractability of all novel targets identified in Project 1. Aim 2 builds on the outputs from Aim 1 and develops the robust crystallization protocols, and orthogonal assays for biochemical activity and biophysical affinity. Aim 3 entails the completion and analyses of the crystallographic fragment screens. Aim 4 finalizes TEPs by validating assays and binding pose with hit compounds derived from observed fragments. In summary, Project 2 combines an established workflow with recent innovations to deliver TEPs that are rigorous, effective and reproducible, providing the foundations for the far-reaching innovations of Project 3 thus ensuring ASAP can deliver on time and on budget. Moreover, TEPs will be promptly published to enable parallel efforts beyond ASAP and increase the overall chances of achieving pandemic preparedness. The project will be delivered by the same team at Diamond Light Source that executed the record-breaking crystallographic (XChem) fragment screen that seeded the COVID Moonshot.

该中心药物发现项目的成功依赖于实验的充分启用以支持 复合式发展。在 Target Enablement 项目中，我们将开发并验证实验 通过生成“目标启用包”(TEP) 来执行程序。这些包括一组实验方案 和输出，生成快速、可靠、全谱读数，支持设计加速 测试分析 (DMTA) 循环。 TEP 是针对目标和药物化学的高效推动者 确定可实现目标的方式；然而，它们常常仍然不完整，因为它们 需要付出很大的努力才能从文献和/或试错实验中进行组装；并确定药用 无论如何，化学家可能会设法开发化合物系列。然而，这掩盖了真实的机会 这样做的成本，包括合成不必要的化合物、追求死胡同的假设， 以及糟糕的数据模型。在 Target Enablement 项目中，我们建议生成下一代 TEP 其中包括用于生成生化行为良好、结晶良好的 3D 蛋白质的试剂和方案 来自基于晶体的片段筛选、生化和生物物理测定的结合位点的相互作用图 和有说服力的命中化合物，表现出一致的低微摩尔亲和力、活性和结合姿势， 通过一组类似物可以合理化。我们将通过以下方式提供严格、有效且可重复的 TEP： (a) 牛津大学自 2015 年以来开发的既定系统工作流程中的承包，以及 (b) 实施和强化最新的创新和新技术，包括在 继新冠登月计划和其他与流行病相关的工作之后。因此，项目 2 的具体目标是生成 针对 10 个目标的下一代 TEP，以推动项目 3 中的快速从命中到先导进展，并由此验证 病毒学和化学生物学的抗病毒假说。该目标分为 4 个目标，其中目标 1 建立 项目 1 中确定的所有新目标的生化和晶体结构可处理性。目标 2 以产出为基础 从目标 1 出发，开发了稳健的结晶方案以及生化活性和正交分析 生物物理亲和力。目标 3 需要完成和分析晶体碎片屏幕。目标 4 通过验证测定和与源自观察片段的命中化合物的结合姿势来最终确定 TEP。在 总之，项目 2 将既定的工作流程与最新的创新相结合，提供严格、 有效且可重复，为项目3的深远创新奠定了基础，从而确保 ASAP 可以按时、按预算交付。此外，TEP 将及时发布，以实现并行工作 尽快超越并增加实现大流行防范的总体机会。该项目将是 由执行破纪录晶体学的 Diamond Light Source 的同一团队提供 (XChem) 片段屏幕为新冠登月计划奠定了基础。