Generating Diverse Pilot-Scale Libraries for Screening

生成用于筛选的多样化中试规模文库

• 批准号: 7684194
• 负责人: STEPHEN MARTIN
• 金额: $ 35.35万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-05 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7684194
• 关键词: Address; Biological; Biological Assay; Biological Factors; Biological Process; Chemistry; Collection; Complex; Computing Methodologies; Development; Diagnostic; Disease; Ensure; Exhibits; Genes; Genome; Health; Human; Individual; Institutes; Knowledge; Libraries; Maps; Metabolic Pathway; Metric; Molecular Bank; Parents; Pattern; Pharmaceutical Preparations; Physiological; Property; Proteins; Relative (related person); Screening procedure; Series; Signal Transduction; Structure; Structure-Activity Relationship; Technology; Texas; United States National Institutes of Health; Ursidae Family; base; chemical synthesis; design; member; novel; repository; sample collection; scaffold; small molecule; sound; therapeutic target; tool

DESCRIPTION (provided by applicant): The past decade has witnessed remarkable advances in scientific knowledge and technology that will have significant impacts upon human health. With the sequencing of the human and other genomes, new genes, gene products, signaling and metabolic pathways are being discovered at a rapid pace, thereby leading to the identification of numerous potential therapeutic targets that would have otherwise been unknown. Biological assays to determine activities have led to the discovery of numerous small molecules that have promising physiochemical and physiological properties. Conversely, small molecules are increasingly serving as invaluable tools to probe biological function and mechanism. Despite the stunning progress that has been made, one significant challenge that remains lies in identifying biologically active small molecules having novel chemotypes and structures. This problem is best addressed by the chemical synthesis of new, functionalized heterocyclic frameworks that may be easily elaborated to optimize biological activity. We will thus apply chemistry we have uniquely developed for the diversity-oriented synthesis of functionalized, heterocyclic scaffolds to prepare pure (>90%) samples of collections of distinct, novel compounds for submission to the NIH Molecular Libraries Small-Molecule Repository (MLSMR). These small molecules will be derived from a series of approximately 25-30 different heterocyclic scaffolds, some of which are both structurally and functionally complex, having different substitution patterns that are explicitly designed to optimally occupy three-dimensional space of the biological target. The design of each collection of molecules is based upon a sound biological rationale. For example, many members of the proposed libraries are natural product-like, whereas others embody known privileged structures. Prior to the synthesis of each library, computational methods, including diversity mapping, will be employed to ensure maximal structural diversity in the collection. Individual members of the collections will be verified as drug-like by application of various standard metrics, including the Lipinski Rule of Five. Each molecule will bear functionality that will allow for further development of structure activity relationships. It is expected that compounds submitted to the MLSMR will exhibit biological activities in a broad range of assays and serve as useful tools to explore biological function, thereby leading to significant improvements in disease treatment.

描述（由申请人提供）：过去十年来，科学知识和技术取得了显着的进步，这将对人类健康产生重大影响。随着人类和其他基因组的测序，新基因，基因产物，信号传导和代谢途径正在快速速度发现，从而导致鉴定出许多潜在的治疗靶标，否则这些靶标本来是未知的。确定活动的生物学测定导致发现了许多具有有希望的理化和生理特性的小分子。相反，小分子越来越多地用作探测生物学功能和机制的宝贵工具。尽管取得了惊人的进步，但仍然存在的一个重大挑战在于鉴定具有新型化学型和结构的生物活性小分子。通过化学合成新的，功能化的杂环框架，可以轻松阐述以优化生物学活性来解决这个问题。因此，我们将应用化学性质，我们为功能化的，杂环脚手架的多样性合成而唯一开发的化学性质来制备纯（> 90％）的样本，这些样品的含量（> 90％）的新型化合物的集合，以使NIH分子文库提交给NIH分子库小型分子储物库（MLSMR）。这些小分子将源自一系列大约25-30个不同的杂环支架，其中一些既有结构和功能复杂，具有明确设计的不同替代模式，以最佳地占据生物学靶标的三维空间。每个分子集合的设计都是基于合理的生物学原理。例如，所提出的图书馆的许多成员类似于天然产品，而其他库则体现了已知的特权结构。在合成每个库之前，将采用计算方法，包括多样性映射，以确保藏品中的最大结构多样性。通过应用各种标准指标，包括五个标准规则，将通过应用各种标准指标来验证该收集的个别成员。每个分子将具有功能，从而可以进一步发展结构活动关系。预计提交给MLSMR的化合物将在广泛的测定中表现出生物学活性，并作为探索生物学功能的有用工具，从而导致疾病治疗的显着改善。