Libraries for HTS: Privileged Structures in Sparsely Populated Chemical Space

描述(由申请人提供)：由未被探索的化学类型组成的高度多样化的化合物文库将被提供给NIH用于在NIH分子图书馆筛选中心网络(MLSCN)中进行筛选。这一应用的中心假设是，化合物文库包含新的化学类型，包含特权结构，并覆盖了大部分未开发的多样性空间，将为研究基因、信号通路和其他复杂生物系统的功能提供新的工具。这些文库包含了增强活性的特征，如特权结构和其他已知对与大分子结构相互作用很重要的特征。因此，这些文库在生物检测中预计会有很高的命中率。这些文库被设计成提供多样化的化学类型，根据它们的多样性分数来判断。多样性分数是通过对NIH PubChem数据库的分析得出的，并表明所提出的支架填充了稀疏填充的多样性空间。在这个项目中，只有来自稀疏和中等密度、具有足够溶解性的化学空间的化合物才会被选择用于合成。提出了提供不同化学类型的五个子项目：(1)含氮环支架文库的合成；(2)基于特权结构的阶乘文库的设计和合成；(3)新型中等环状组合文库；(4)面向多样性的文库合成；(5)天然产物衍生文库。

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.