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）：由尚未探索的化学型组成的高度多样化的化合物库将提供给 NIH，以便在 NIH 分子库筛选中心网络 (MLSCN) 中进行筛选。 该应用的中心假设是，包含新化学型、包含特殊结构并涵盖很大程度上未探索的多样性空间的化合物库将为研究基因、信号传导途径和其他复杂生物系统的功能提供新工具。 这些库包含了活性增强功能，例如特权结构和其他已知对于与大分子结构相互作用非常重要的功能。 因此，预计这些文库在生物测定中具有高命中率。 这些文库旨在根据其多样性得分来提供不同的化学型。 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了稀疏的多样性空间。 在该项目中，仅选择来自稀疏且中等分布且具有足够溶解度的化学空间的化合物进行合成。提出了五个提供不同化学型的子项目：（1）含氮环状支架文库的合成； （2）从特权结构设计和合成因子库； (3) 新型中环尺寸组合文库； (4) 面向多样性的文库合成； (5)天然产物衍生的文库。