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）：该项目的目标是开发使用广角 X 射线溶液散射 (WAXS) 作为常规筛选工具，用于检测治疗感兴趣的蛋白质与小分子配体之间的功能相互作用。药物发现和开发的目的。先导化合物的发现过程是药物设计过程中的一个早期且重要的瓶颈，并减缓了新治疗方法的最终开发。 WAXS 构成了影响这一过程的新的强大工具。该技术是通用目标，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。蛋白质靶标只需以中等浓度溶于水即可适合这些研究，并且不需要专门的样品处理或制备。为了使这种方法适应中等吞吐量的商业服务，我们建议自动化数据收集和数据分析过程，使其尽可能快速且用户友好。具体目标是（1）通过构建具有样本处理机器人控制功能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) 开发一个软件包，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自动化下游数据处理和分析； (3) 通过针对 3-4 个药学相关蛋白质靶标筛选商业制药公司制备的 50-75 种化合物库，并统计评估该技术的能力，对该方法进行双盲概念验证测试将已知的目标结合物与库中的其他化合物区分开来。公共健康相关性：该项目将开发一种新技术以实现商业化，该技术具有影响先导药物发现过程的巨大潜力。影响该领域的新工具开发的减少导致药物发现过程持续放缓，药物化学创新停滞，这意味着公众可以获得的有效新疾病疗法越来越少。