Libraries for HTS: Privileged Structures in Sparsely Populated Chemical Space

HTS 库：稀疏化学空间中的特权结构

• 批准号: 7291334
• 负责人: Gunda I. Georg
• 金额: $ 45.24万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7291334
• 关键词: Affinity; Amino Alcohols; Biochemical; Biological; Biological Assay; Biological Factors; Charge; Chemicals; Chloroform; Complex; Computer Simulation; Databases; Diversity Library; Drug Delivery Systems; Elements; Hydrogen Bonding; Libraries; Ligands; Methanol; Molecular Bank; Molecular Structure; Molecular Weight; Nitrogen; Proteins; Rare Diseases; Rate; Research; Scheme; Score; Screening procedure; Signaling Pathway Gene; Solubility; Source; Structure; Synthesis Chemistry; System; Testing; United States National Institutes of Health; combinatorial; design; electron donor; enantiomer; follow-up; gene function; innovation; member; novel; programs; receptor; scaffold; size; tool

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.

描述（由申请人提供）：将向NIH提供高度多样化的化合物库，以在NIH中提供NIH分子库筛选中心网络（MLSCN）的筛查。 该应用的中心假设是，包含新型化学型，结合特权结构并涵盖在很大程度上未开发的多样性空间的复合文库将提供研究基因，信号通路和其他复杂生物系统功能的新工具。 这些库包含了增强活动的特征，例如特权结构和其他特征，这对于与大分子结构的相互作用很重要。 因此，图书馆的生物测定法具有很高的命中率。 这些图书馆旨在提供不同的化学型，根据其多样性评分来判断。 对NIH PubChem数据库的分析得出了多样性评分，并证明所提出的支架填充了人口稀少的多样性空间。 在该项目中，只有来自具有足够溶解性的稀疏和中等化的化学空间的化合物。提出了五个提供各种化学型的子标本：（1）与含氮循环支架的库合成； （2）从特权结构设计和合成阶乘库； （3）新型的中环组合库； （4）面向多样性的图书馆合成； （5）天然产品衍生的库。