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Pilot-Scale Libraries Based on Nucleoside Templates for the ML Initiative

用于 ML 计划的基于核苷模板的中试规模文库

基本信息

批准号：
7938009
负责人：
Robert C Reynolds
金额：
$ 58.12万
依托单位：
SOUTHERN RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-05 至 2011-08-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Many of the large, publicly accessible commercial libraries are based on planar heterocyclic aromatic scaffolds that lack variety as pharmacophores in terms of three dimensional space filling and conformational mobility. As such, the Pilot Library Program of the NIH was created to pursue unique chemical diversity not represented by currently available libraries. Natural products have been mined for centuries to fulfill the need for bioactive substances and currently comprise a large proportion of clinically used drugs. By definition, natural products are inherently biased towards biological availability and activity, and libraries derived there from possess unique three-dimensional structural features and are more complex than simpler compounds derived from purely synthetic reagents. Hence, we plan to take advantage of unique, commonly available natural product templates for the preparation of new libraries that are underrepresented in current commercial libraries and the Molecular Library Small Molecule Repository (MLSMR). The specific aims of this program include strategic diversity-oriented elaboration of readily accessible natural product nucleoside scaffolds. We will prepare 1400 highly pure and novel samples from the three specific aims and supply between 10 to 20 mg of each sample as dry powders to the MLSMR as per program requirements. These samples will be carefully screened to guarantee that they are not covered through patents in order to ensure unencumbered usage, and all data on the samples (synthetic methods and analyses) will be made freely accessible to the scientific community as per NIH Resource Sharing requirements. The enrichment of the chemical diversity of the NIH MLSMR should enhance the prospect of identifying biochemical tools to probe a variety of biological targets of relevance in health and disease. Moreover, the screening of the libraries and free accessibility of those data will stimulate research that should ultimately lead to improvements in our knowledge of systems biology and the living organism. Advances from this effort may eventually lead to new therapeutics, especially for rare or marginalized disorders thus benefiting overall public health.

描述（由申请人提供）：许多大型的、可公开访问的商业文库都是基于平面杂环芳族支架，其在三维空间填充和构象迁移性方面缺乏药效团的多样性。因此，美国国立卫生研究院 (NIH) 的试点图书馆计划旨在追求当前可用图书馆无法代表的独特化学多样性。几个世纪以来，天然产物一直被开采以满足生物活性物质的需求，目前临床使用的药物占很大比例。根据定义，天然产物本质上偏向于生物利用度和活性，并且从中衍生的文库具有独特的三维结构特征，并且比从纯合成试剂衍生的简单化合物更复杂。因此，我们计划利用独特的、常用的天然产物模板来制备新的文库，这些新文库在当前的商业文库和分子文库小分子存储库（MLSMR）中代表性不足。该计划的具体目标包括以战略多样性为导向的易于获取的天然产物核苷支架的阐述。我们将从三个具体目标中制备 1400 个高纯度和新颖的样品，并根据计划要求向 MLSMR 提供 10 至 20 毫克的干粉样品。这些样本将经过仔细筛选，以确保它们不受专利保护，从而确保不受阻碍的使用，并且样本的所有数据（合成方法和分析）将根据 NIH 资源共享要求免费向科学界开放。 NIH MLSMR 化学多样性的丰富应该会增强识别的前景用于探测与健康和疾病相关的各种生物目标的生化工具。此外，图书馆的筛选和这些数据的免费获取将刺激研究，最终应提高我们对系统生物学和生物体的了解。这项努力的进展最终可能会带来新的治疗方法，特别是针对罕见或边缘性疾病，从而有利于整体公共卫生。