A high-throughput platform for crystallography-based fragment screening

基于晶体学的片段筛选的高通量平台

• 批准号: 9761546
• 负责人: ASHLEY M. DEACON
• 金额: $ 48.65万
• 依托单位: ACCELERO BIOSTRUCTURES, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9761546
• 关键词: 3-Dimensional; Academia; Adopted; Affinity; Binding; Biological; Biological Assay; Biophysics; Chemicals; Clinical Trials; Crystallization; Crystallography; Custom; Data; Data Analyses; Data Collection; Data Set; Databases; Development; Drug Industry; Drug Targeting; Failure; Goals; Gold; Harvest; Imaging technology; In Situ; Industrialization; Industry; Informatics; Intellectual Property; Intervention; Joints; Lead; Legal patent; Libraries; Liquid substance; Location; Malignant Neoplasms; Manuals; Marketing; Measures; Methods; Molecular; Molecular Weight; Monitor; National Institute of General Medical Sciences; Nuclear Magnetic Resonance; One-Step dentin bonding system; Outcome; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Positioning Attribute; Preclinical Testing; Preparation; Process; Production; Protein Fragment; Protein Structure Initiative; Proteins; Resources; Roentgen Rays; Route; Sampling; Scanning; Services; Small Business Innovation Research Grant; Software Tools; Structure; Surface Plasmon Resonance; Synchrotrons; System; Techniques; Technology; Testing; Time; Toxic effect; Translational Research; Vertebral column; X ray diffraction analysis; X-Ray Crystallography; analysis pipeline; base; biophysical techniques; commercial application; commercialization; computational platform; computerized data processing; cost; cost effective; data management; data structure; density; design; drug candidate; drug development; drug discovery; drug market; experimental study; high throughput screening; imaging system; improved; interest; new therapeutic target; novel; novel lead compound; novel therapeutics; off-patent; oncology; programs; screening; software development; structural biology; structural genomics; success; three dimensional structure; tool

Project Summary/Abstract Fragment-based drug discovery (FBDD) is a widely used method in the pharmaceutical industry for the de novo design of molecules that target new drug candidates. FBDD allows a more effective exploration of chemical space with a higher hit rate compared to high-throughput screening, and this can have significant effects in early drug discovery and in the case of challenging or “non-druggable” targets. FBDD has led to around 30 new drugs entering clinical trials and 2 that have entered the market. FBDD can also be used to discover and develop novel molecules for well-validated and important drug targets that already have marketed drugs against them, both for increasing efficacy with lower toxicity as well as creation of new intellectual property for off-patent drugs. Protein x-ray crystallography (PX) is the gold standard for determining the exact 3D location and orientation of a given fragment bound to a drug target. PX can also detect a wider range of binding affinities compared to other biophysical methods for fragment and compound screening and is independent of protein size. However, crystallography is expensive and inefficient for screening a large fragment library due to significant bottlenecks in mass production of crystals for co-crystallization, crystal soaking with fragments, crystal harvesting, X-ray data collection, structure determination and analysis. Complementary biophysical techniques are often used to prescreen for fragments that bind and PX is then used in a second step to determine the exact binding pose of each fragment. Accelero Biostructures is developing a first-to-market, efficient, one-step PX-based fragment library-screening platform that can revolutionize the field by dramatically increasing the efficiency and reducing the cost of developing novel lead molecules for preclinical testing. In Phase I we evaluated a high-density crystallization grid that dramatically increased the efficiency of target-fragment co-crystallization, crystal soaking with fragments and synchrotron- based data collection, leading to a hit rate of ~5% in a single step while simultaneously producing 3D details of protein-fragment interactions. After successfully completing our Phase I aims, we are now moving ahead with our Phase II plan to integrate this experimental technology with a distributed computational crystallography pipeline and data management/informatics backbone that will allow us to efficiently process a large fragment library screen. We will use several druggable and non-druggable oncology targets implicated in various cancers, from our industry and academic customers, as proof-of-concept systems to demonstrate the utility of our overall platform. Our plans are well-aligned with all of NCATS Drug Discovery and Development SBIR topics of interest: “Tools and technologies to enable assaying of compound activity on currently “non- druggable” targets”; “Co-crystallization high-throughput screening techniques”; “Tools and technologies that increase the predictivity or efficiency of medicinal chemistry, biologic or other intervention optimization”; and “Development of high-throughput imaging technologies that focus on making translational research more efficient”.

项目概要/摘要 基于片段的药物发现（FBDD）是制药行业广泛使用的药物发现方法 针对新候选药物的分子的新颖设计可以更有效地探索。 与高通量筛选相比，化学空间具有更高的命中率，这可以具有显着的效果 FBDD 在早期药物发现以及具有挑战性或“不可成药”靶标的情况下产生了影响。 约30种进入临床试验的新药和2种已进入市场的新药也可用于FBDD。 发现和开发已上市的经过充分验证的重要药物靶标的新分子 对抗它们，既是为了提高药物疗效、降低毒性，也是为了创造新的知识产权 蛋白质 X 射线晶体学 (PX) 是确定准确药物的金标准。 与药物靶点结合的给定片段的 3D 位置和方向还可以检测更广泛的范围。 与片段和化合物筛选的其他生物物理方法相比，结合亲和力 然而，晶体学对于筛选大的蛋白质来说是昂贵且低效的。 由于共晶晶体批量生产的重大瓶颈，片段库 碎片浸泡、晶体收获、X射线数据收集、结构测定和分析。 补充生物物理技术通常用于预筛选结合的片段，然后 PX Accelero Biostructs 在第二步中用于确定每个片段的确切结合姿势。 开发第一个上市的、高效的、一步式的基于 PX 的片段库筛选平台，该平台可以 通过大幅提高效率并降低开发新型先导化合物的成本来彻底改变该领域 在第一阶段，我们评估了高密度结晶网格，该网格显着提高了分子的临床前测试效率。 提高了目标-碎片共结晶、碎片晶体浸泡和同步加速器的效率 基于数据收集，一步实现约 5% 的命中率，同时生成 3D 细节 在成功完成第一阶段的目标后，我们现在正在继续推进。 我们的第二阶段计划将该实验技术与分布式计算晶体学相结合 管道和数据管理/信息学骨干将使我们能够有效地处理大片段 我们将使用与各种涉及的药物和非药物肿瘤学靶点。 来自我们的行业和学术客户的癌症作为概念验证系统来展示 我们的整体平台与 NCATS 药物发现和开发 SBIR 保持一致。 感兴趣的主题：“能够分析当前“非”化合物活性的工具和技术 “可成药”靶标”；“共结晶高通量筛选技术”； 提高药物化学、生物或其他干预优化的预测性或效率”； “开发高通量成像技术，专注于使转化研究更加 高效的”。