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

描述(申请人提供)：许多大型的、可公开访问的商业图书馆是基于平面杂环芳香支架，这些支架在三维空间填充和构象流动性方面缺乏作为药效团的多样性。因此，创建了美国国立卫生研究院的试行图书馆计划，以追求现有图书馆所没有的独特的化学多样性。几个世纪以来，人们一直在开采天然产物，以满足对生物活性物质的需求，目前天然产物构成了临床使用的药物的很大比例。根据定义，天然产物天生偏向于生物可利用性和活性，从天然产物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更简单的化合物更复杂。因此，我们计划利用独特的、普遍可用的天然产品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)中没有得到充分的代表。该计划的具体目标包括以战略多样性为导向的易于获得的天然产品核苷支架的精加工。我们将从三个特定的目标制备1400个高纯度和新颖的样品，并根据计划要求向MLSMR提供每个样品10至20 mg的干粉。这些样本将经过仔细筛选，以保证它们不受专利保护，以确保不受阻碍地使用，并且根据国家卫生研究院的资源共享要求，科学界将免费获取有关样本的所有数据(合成方法和分析)。NIH MLSMR化学多样性的丰富应该会增强识别 生物化学工具，用于探索与健康和疾病相关的各种生物靶标。此外，对图书馆的筛选和对这些数据的免费获取将刺激研究，最终将导致我们对系统生物学和生物有机体的知识的改善。这一努力的进展可能最终导致新的治疗方法，特别是对罕见或边缘化疾病的治疗，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.