A universal high-throughput platform to improve biological functions of small molecules

项目摘要/摘要 高通量筛查方法和仪器的可获得性增加已经彻底改变了 科学界正在寻找调节蛋白质功能和细胞途径的小分子。这个 对照体外和细胞分析挖掘大量小分子文库的主要目标是识别 化合物用于开发化学工具来操纵生物系统的空间、时间和 依赖于浓度的控制，以及提供关于药物开发的关键信息。不幸的是， 大多数初步筛选需要广泛的优化，以产生具有必要效力和 生物应用的选择性。前导优化是药物和探针开发中的一个重大障碍 由于耗材、人工费用和时间的昂贵数量，以及对直觉和 药物化学家的合成技能。关键是，大多数学术实验室无法获得药物 化学成分，经常使用可能产生误导结果的低质量化学探头。一种可编程逻辑控制器的设计 因此，通用和高性价比的高通量药物化学平台是一个重要的优先事项。 我的应用程序专注于开发、验证和使用一个实用的、全面的平台来 高通量合成铅化合物模拟库和生物活性测试。我有过 二氟亚胺硫(VI)氟化物交换(SuFEx)反应 (“异氟醚”)-含有分子和胺，在DMSO和PBS中产生所需产品的80%。我的 令人兴奋的初步研究表明，我可以合成一个关于皮考莫尔的铅化合物类似物的集中文库。 规模化，直接用体外试验评估产品，并开发具有改进的生物学特性的类药物配体 功能。在这里，我的目标是：1)开发、精简和验证平台(SA1)；2)严格评估 我的平台针对一组具有不同体外和细胞基础的蛋白质靶点的综合性 分析(SA2)；以及3)将该平台应用于功能片段分子以识别新的蛋白质靶标 生物功能。成功地完成了这项由狼人、夏普莱斯人、 Cravatt和Calibr将为研究界提供一个强大的药物化学平台。化学制品 该平台开发的探针最终将提高我们对基本原理的分子水平的理解 生物过程和发现控制它们的方法。

PROJECT SUMMARY/ABSTRACT The increased accessibility of high-throughput screening methods and instruments has revolutionized how the scientific community searches for small molecules that modulate protein function and cellular pathways. The primary goal of mining large collections of small-molecule libraries against in vitro and cellular assays is to identify compounds for the development of chemical tools to manipulate biological systems with spatial, temporal, and concentration-dependent control, as well as provide critical information on drug development. Unfortunately, most initial screening hits require extensive optimization to yield molecules with the necessary potency and selectivity for biological applications. Lead optimization is a significant hurdle in the drug and probe development process due to the costly amounts of consumables, labor expenses and time, and reliance on the intuition and synthetic skills of medicinal chemists. Critically, a majority of academic labs do not have access to medicinal chemistry and often use low-quality chemical probes that may provide misleading results. The design of a universal and cost-effective high-throughput medicinal chemistry platform is therefore a significant priority. My application is focused on the development, validation, and use of a practical, comprehensive platform to synthesize lead compound analog library and test biological activity in an high-throughput manner. I have recently repurposed sulfur(VI) fluoride exchange (SuFEx) reactions between iminosulfur oxydifluoride (“isodifluor”)-containing molecules and amines that yield >80% of the desired product in DMSO and PBS. My exciting initial studies show that I can synthesize a focused libraries of lead compound analogs on picomole scale, directly assess the products with in vitro assays, and develop drug-like ligands with improved biological functions. Here, my goals are to: 1) develop, streamline and validate the platform (SA1); 2) rigorously assess the comprehensiveness of my platform against a panel of protein targets with diverse in vitro and cell-based assays (SA2); and 3) apply the platform to functional fragment molecules to identify protein targets with novel biological functions. The successful completion of this highly collaborative study among the Wolan, Sharpless, Cravatt, and Calibr will provide a robust medicinal chemistry platform for the research community. Chemical probes developed by the platform will ultimately improve our molecular-level understanding of fundamental biological processes and discovering approaches to their control.