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

描述（由申请人提供）：该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，用于检测治疗感兴趣的蛋白质和小分子配体之间的功能相互作用，以用于药物发现和开发。在药物设计过程中，先导物的发现过程是一个早期和重大的瓶颈，并减缓了新治疗方法的最终发展。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可以应用于几乎任何蛋白质。蛋白质目标只需要在中等浓度下是水溶性的，使它们适合这些研究，不需要专门的样品处理或准备。为了使这种方法适应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，以使它们尽可能快速和用户友好。具体目标是：(1)通过构建具有机器人控制标本处理的便携式广角相机，开发自动化样品处理硬件和相关控制系统；(2)开发一个软件包，通过更新和改进目前使用的软件，并将这些过程纳入一个用户友好、全面的界面，实现下游数据处理和分析的自动化；(3)通过筛选一家商业制药公司制备的50-75个化合物文库，针对3-4个药学上相关的蛋白质靶标，对该方法进行双盲概念验证，并统计评估该技术区分已知靶标结合物与文库中其他化合物的能力。公共卫生相关性：该项目将开发一项商业化的新技术，对药物先导物的发现过程有很大的影响。影响这一领域的新工具的开发减少，导致药物发现过程不断放缓，药物化学创新停滞不前，这意味着公众可以获得的有效的新疾病治疗方法越来越少。

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.