Wide Angle X-ray Scattering for Commercial Applications in Drug Lead Discovery

广角 X 射线散射在先导药物发现中的商业应用

• 批准号: 7671745
• 负责人: LEE MAKOWSKI
• 金额: $ 10万
• 依托单位: SHAMROCK STRUCTURES, LLC
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7671745
• 关键词: Area; Biochemical; Blood capillaries; Buffers; Collection; Computer software; Data; Data Analyses; Data Collection; Detection; Development; Disease; Double-Blind Method; Drug Delivery Systems; Drug Design; Goals; Lead; Libraries; Ligands; Measures; Methods; Pattern; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Preparation; Process; Proteins; Protocols documentation; Pump; Radiation; Robotics; Roentgen Rays; Sampling; Screening procedure; Services; Solutions; Specimen; Specimen Handling; Structure; Syringes; System; Techniques; Technology; Testing; Time; Update; aqueous; capillary; commercial application; commercialization; computer program; computerized data processing; detector; drug discovery; improved; innovation; interest; novel; novel therapeutics; protein profiling; protocol development; public health relevance; research study; small molecule; success; therapeutic protein; tool; two-dimensional; user-friendly

DESCRIPTION (provided by applicant): The goal of this project is to develop the use of wide-angle x-ray solution scattering (WAXS) as a routine screening tool for detection of functional interactions between proteins of therapeutic interest and small molecule ligands for the purposes of drug discovery and development. The process of lead discovery presents an early and significant bottleneck in the process of pharmaceutical drug design and slows the ultimate development of new therapeutic treatments. WAXS constitutes a new and powerful tool to impact this process. The technique is target-general, meaning that a single, standard protocol for the collection of WAXS data can be applied to virtually any protein. The protein targets need only be aqueous soluble at moderate concentration to make them amenable to these studies and no specialized sample handling or preparation is necessary. To adapt this approach to moderate throughput commercial service, we propose to automate both the data collection and the data analysis processes to make them as rapid and user-friendly as possible. The specific aims are (1) to develop automated sample handling hardware and associated control systems by constructing a portable, wide-angle camera with robotic control of specimen handling; (2) to develop a software package to automate downstream data processing and analysis by updating and improving currently utilized software and incorporating these processes into a user- friendly, comprehensive interface; and (3) to conduct a double-blind proof of concept test of the method by screening a library of 50-75 compounds, prepared by a commercial Pharmaceutical Company, against 3-4 pharmaceutically relevant protein targets and statistically evaluating the ability of the technique to distinguish the known target binders from other compounds in the library. PUBLIC HEALTH RELEVANCE: This project will develop for commercialization a new technique having high potential to impact the pharmaceutical lead discovery process. Decreased development of novel tools to impact this area has resulted in continual slowing of the process of drug discovery and in stagnation of medicinal chemistry innovation meaning that fewer effective new disease therapies are available to the public.

描述（由申请人提供）：本项目的目标是开发广角X射线溶液散射（WAXS）作为常规筛选工具的用途，用于检测具有治疗意义的蛋白质与小分子配体之间的功能性相互作用，以用于药物发现和开发。先导发现的过程在药物设计过程中呈现出早期和显著的瓶颈，并减缓了新治疗方法的最终开发。WAXS是影响这一过程的一个新的强大工具。该技术是目标通用的，这意味着用于收集WAXS数据的单一标准协议几乎可以应用于任何蛋白质。蛋白质靶标仅需要在中等浓度下是水溶性的，以使它们适合于这些研究，并且不需要专门的样品处理或制备。为了使这种方法适用于中等吞吐量的商业服务，我们建议将数据收集和数据分析过程自动化，使其尽可能快速和方便用户。具体目标是（1）通过构造具有样本处理的机器人控制的便携式广角相机来开发自动化样本处理硬件和相关控制系统;（2）通过更新和改进当前使用的软件并将这些过程合并到用户友好的综合界面中来开发用于自动化下游数据处理和分析的软件包;和（3）通过针对3-4种药学相关蛋白质靶标筛选由商业制药公司制备的50-75种化合物的文库，并统计学地评价该技术区分已知靶标结合剂与文库中其它化合物的能力，来进行该方法的双盲概念验证试验。公共卫生关系：该项目将开发一种新技术，以实现商业化，该技术具有很大的潜力来影响药物先导发现过程。影响这一领域的新工具的开发减少导致药物发现过程的持续放缓和药物化学创新的停滞，这意味着公众可获得的有效新疾病疗法越来越少。