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

描述（由申请人提供）：许多大型的、可公开获得的商业文库基于平面杂环芳族支架，其在三维空间填充和构象移动性方面缺乏作为药效团的多样性。因此，美国国立卫生研究院的试点图书馆计划的创建是为了追求独特的化学多样性，而不是目前可用的图书馆。几个世纪以来，人们一直在开采天然产品，以满足对生物活性物质的需求，目前天然产品在临床使用的药物中占很大比例。根据定义，天然产物固有地偏向于生物可用性和活性，并且从其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，这些文库在当前的商业文库和分子文库小分子库（MLSMR）中代表性不足。该计划的具体目标包括战略多样性为导向的阐述容易获得的天然产物核苷支架。我们将从三个特定目标中制备1400个高纯度和新型样品，并根据项目要求将10至20 mg的每份样品以干粉形式提供给MLSMR。这些样本将被仔细筛选，以保证它们不受专利保护，以确保不受限制的使用，并且根据NIH资源共享要求，科学界将免费获取样本的所有数据（合成方法和分析）。NIH MLSMR化学多样性的丰富将增强其鉴定的前景 生物化学工具来探测与健康和疾病相关的各种生物靶标。此外，图书馆的筛选和这些数据的免费访问将刺激研究，最终将导致我们对系统生物学和生物有机体的知识的改进。这一努力的进展可能最终导致新的治疗方法，特别是对于罕见或边缘化的疾病，从而使整体公共卫生受益。

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.