Probing Diversity Space with Novel Pilot Scale Libraries

用新颖的中试规模库探索多样性空间

• 批准号: 7125562
• 负责人: PAUL R. HANSON
• 金额: $ 43.17万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-23 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7125562
• 关键词: NIH Roadmap Initiative tag; biological products; biomimetics; chemical registry /resource; chemical structure; chemical synthesis; cheminformatics; combinatorial chemistry; high throughput technology; phosphorus; sulfur

DESCRIPTION (provided by applicant): The goal of this application is to produce pilot-scale libraries derived from an array of novel heterocyclic scaffolds. We aim to produce "drug-like" and "natural product-like" libraries for HTS in order to maximize the probability of procuring compounds that have a high likelihood of interacting with biomolecular targets. Ultimately, these libraries will be evaluated via the Molecular Library Screening Network (MLSCN) in order to uncover lead structures for further development. We are well positioned to meet this goal by employing methodologies developed in our laboratories that focus on scaffolds that are designed according to medicinal chemistry principles, and use efficient scaffold generation/diversification strategies and facilitated synthetic protocols for library production. In many cases, the proposed libraries have been identified as part of target-based discovery programs within individual research efforts at the University of Kansas (KU). These efforts are augmented by expertise in a number of Centers of Excellence at the University of Kansas, including centers in: (i) Combinatorial Methodologies and Library Development, (ii) Cancer Experimental Therapeutics, (iii) Protein Structure and Function, and (iv) a state-of-the-art High-Throughput Screening Laboratory. This combination of infrastructure and expertise enables us to produce scalable, diverse libraries based on a wide variety of novel scaffolds and allows us to probe biological and chemical space in a dynamic manner. To accomplish this, libraries containing 60-100 compounds in sufficient quantities (10-15 mgs) for HTS on numerous platforms within the MLSCN will be made. Specific efforts proposed herein include library validation by computational methods including diversity-space mapping, the use of facilitated synthetic protocols based on high-load ROMP-reagents and other supported reagents, and both solution-phase and Irori-based solid phase synthetic protocols. A number of libraries are proposed displaying a diverse array of scaffolds, including: (i) turn-inspired peptidomimetics, (ii) sulfur- and phosphorus-containing heterocycles, and (iii) heterocyclic natural product-like scaffolds.

描述（由申请人提供）：本申请的目标是产生源自一系列新型杂环支架的中试规模文库。我们的目标是为 HTS 生成“类药物”和“类天然产物”库，以最大限度地提高获得与生物分子靶点相互作用的可能性较高的化合物的可能性。最终，这些文库将通过分子文库筛选网络 (MLSCN) 进行评估，以发现用于进一步开发的先导结构。我们有能力通过采用实验室开发的方法来实现这一目标，这些方法专注于根据药物化学原理设计的支架，并使用高效的支架生成/多样化策略和促进文库生产的合成方案。在许多情况下，拟议的图书馆已被确定为堪萨斯大学 (KU) 个人研究工作中基于目标的发现计划的一部分。这些努力得到了堪萨斯大学许多卓越中心的专业知识的增强，这些中心包括：（i）组合方法和图书馆开发，（ii）癌症实验治疗，（iii）蛋白质结构和功能，以及（iv） ）最先进的高通量筛选实验室。这种基础设施和专业知识的结合使我们能够基于各种新颖的支架产生可扩展的、多样化的文库，并使我们能够以动态的方式探测生物和化学空间。为了实现这一目标，将在 MLSCN 内的众多平台上建立包含 60-100 种足够数量（10-15 毫克）HTS 化合物的文库。本文提出的具体工作包括通过计算方法进行文库验证，包括多样性空间映射、使用基于高负载 ROMP 试剂和其他支持试剂的促进合成方案，以及溶液相和基于 Irori 的固相合成方案。提出了许多展示多种支架的文库，包括：（i）转角模拟肽，（ii）含硫和磷的杂环，以及（iii）杂环天然产物样支架。