Libraries for HTS: Privileged Structures in Sparsely Populated Chemical Space

描述（由申请人提供）：由未开发的化学型组成的高度多样化的化合物文库将提供给NIH在NIH分子文库筛选中心网络（MLSCN）中进行筛选。该应用程序的中心假设是，化合物文库包含新的化学型，包含特权结构，并覆盖很大程度上未开发的多样性空间，将为研究基因功能，信号通路和其他复杂生物系统提供新的工具。这些库包含了增强活性的特征，如特权结构和其他已知的对与大分子结构的相互作用很重要的特征。因此，这些文库有望在生物分析中具有较高的命中率。这些文库的设计是为了提供多样化的化学型，根据它们的多样性得分来判断。多样性得分来自对NIH PubChem数据库的分析，并表明所提出的支架填充了稀疏的多样性空间。在本项目中，只选择具有适当溶解度且化学空间稀疏的化合物进行合成。提出了五个子项目，提供不同的化学型：(1)含氮循环支架文库的合成；(2)从特权结构中设计和合成阶乘库；(3)新颖的中环大小组合库；(4)面向多样性的图书馆综合；(5)天然产物衍生库。

DESCRIPTION (provided by applicant): Highly diverse compound libraries consisting of under-explored chemotypes will be provided to the NIH for screening in the NIH Molecular Library Screening Center Network (MLSCN). The central hypothesis of this application is that compound libraries, which contain novel chemotypes, incorporate privileged structures, and cover largely unexplored diversity space, will provide new tools to study the functions of genes, signaling pathways, and other complex biological systems. The libraries incorporate activity-enhancing features such as privileged structures and others, known to be important for interactions with macromolecular structures. The libraries are therefore expected to have high hit rates in biological assays. The libraries have been designed to provide diverse chemotypes as judged by their diversity scores. The diversity scores were derived from analysis against the NIH PubChem database and demonstrate that the proposed scaffolds populate sparsely populated diversity space. Only compounds from sparsely and moderately populated chemical space possessing adequate solubility will be selected for synthesis in this project. Five subprojects are proposed that offer varied chemotypes: (1) Synthesis of libraries with nitrogen-containing cyclic scaffolds; (2) Design and synthesis of factorial libraries from privileged structures; (3) Novel medium-ring size combinatorial libraries; (4) Diversity-oriented library synthesis; (5) Natural product-derived libraries.