Libraries for HTS: Privileged Structures in Sparsely Populated Chemical Space

描述（由申请人提供）：将向NIH提供由未开发的化学型组成的高度多样化的化合物文库，以在NIH分子文库筛选中心网络（MLSCN）中进行筛选。 本申请的中心假设是，化合物文库，其中包含新的化学型，纳入特权结构，并覆盖了很大程度上未开发的多样性空间，将提供新的工具来研究基因，信号通路和其他复杂的生物系统的功能。 该库包含活性增强功能，如特权结构和其他已知对与大分子结构的相互作用很重要的功能。 因此，预期文库在生物测定中具有高命中率。 文库被设计为提供多样的化学型，如通过其多样性评分所判断的。 多样性得分来自对NIH PubChem数据库的分析，并证明所提出的支架填充稀疏填充的多样性空间。 本项目仅选择来自稀疏和适度分布的化学空间且具有足够溶解度的化合物进行合成。提出了五个子项目，提供不同的化学型：（1）含氮环状支架库的合成;（2）从特权结构设计和合成因子库;（3）新型中环大小的组合库;（4）多样性导向的库合成;（5）天然产物衍生的库。

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.