Scripps Research Institute Molecular Screen Center(RMI)

描述（由申请人提供）：MLSCN提案的关键假设是，当与最先进的后基因组序列、细胞、分子和体内生物学相结合时，高通量化学方法通过发现概念验证（POC）分子为促进生物医学科学的进展提供了快速简便的机制。此外，POC分子的发现将大大加快生物医学进步的应用，以提高公众健康和生活质量。TSRI和其他地方的实验工作在过去的2年里提供了大量的同行评审论文，支持这些方法以极大的速度向前推进领域的能力。此外，他们还证明了一个整合良好的过程的能力，以发现具有精确选择性、效力和体内功效的化学探针分子，并定义新的生物靶标。当现代高通量化学生物学可以与遗传方法整合时，例如靶基因的同源重组缺失或具有显着体外活性的化合物的表达谱分析，就会出现令人信服的结果。这些方法已经定义了新的关键点的生物控制在淋巴细胞再循环和免疫抑制的调节，以及在神经发生。TSRI的检测专业知识涵盖了许多不同的形式，包括全细胞钙通量检测、报告基因检测、酶检测、蛋白质-蛋白质相互作用和细胞分化读数。我们进一步期望这种方法与更高通量的分子生物学方法如siRNA协同作用，因此成为后基因组序列生物医学科学的科学动力的基本驱动力。因此，TSRI提案的主题是跨目标类别灵活、综合地发现概念验证分子，重点是GPCR和细胞分化途径。我们建议通过专门致力于这三个具体目标来实现这一目标：目标1：建立一个检测实施小组，能够在第2年和第3年期间每年优化20个检测。目标二：实施HTS，每年筛选20项检测，每次检测至少筛选100，000种化合物，并及时将有质量保证的数据转移到PubChem数据库。目标3：开发药代动力学和探索性合成化学基础设施，以鉴定能够在基于细胞的系统或体内允许生物概念验证（POC）的命中或命中衍生分子。这些目标的执行将为化学生物学工具向更广泛的生物医学研究领域的传播提供社区数据、工具和资源，从而提高NIH人类健康可测量终点路线图的成功和影响。

DESCRIPTION (provided by applicant): The key hypothesis of the MLSCN proposal is that high throughput chemical approaches, when integrated with state-of-the art post-genome sequence, cell, molecular and in vivo biology, provides a rapid and facile mechanism for enhancing the progress of biomedical science by the discovery of proof-of-concept (POC) molecules. Moreover, it POC molecule discovery will significantly speed up the application of biomedical advances to enhancing the public health and quality of life. Experimental efforts at TSRI and elsewhere have provided substantial peer-reviewed papers over the past 2 years that support the ability of these approaches to move fields forward with great rapidity. In addition, they exemplify the ability of a well integrated process to discover chemical probe molecules of exquisite selectivity, potency and in vivo efficacy, and to define novel biological targets. Compelling results emerge when modern high throughput chemical biology can be integrated with genetic approaches such as homologous recombinant deletion of target genes, or expression profiling of compounds with significant in vitro activity. These approaches have defined new key points of biological control in the regulation of lymphocyte recirculation and immunosuppression, as well as in neurogenesis. Assay expertise within TSRI has covered many different formats from whole cell calcium flux assays, reporter gene assays, enzyme assays, protein-protein interactions and cellular differentiation readouts. We further expect this approach to synergize with higher throughput molecular biological approaches such as siRNA, and therefore be a fundamental driver for scientific momentum in post-genome sequence biomedical science. The theme of the TSRI proposal is therefore the flexible, integrated discovery of proof-of-concept molecules across target classes, with an emphasis on GPCRs and pathways of cellular differentiation. We propose to do so by committing specifically to these three Specific Aims: Aim #1: Establish an Assay Implementation Group with the ability to optimize 20 assays per year during Years 2 and 3. Aim #2: Implement HTS to screen 20 assays and a minimum of 100,000 compounds per assay per year with transfer of the quality-assured data in a timely matter to PubChem database. Aim #3: development of pharmacokinetics and exploratory synthetic chemistry infrastructure to identify hits or hit-derived molecules capable of allowing biological proof of concept (POC) in cell-based systems or in vivo. Execution on these goals will provide community data, tools and resources for the dissemination of the tools of chemical biology to a broader segment of the biomedical research, thus enhancing the success and impact of the NIH Roadmap of measurable endpoints in human health.