Function and Informatics Driven Assembly of New Pilot Scale Libraries

描述（由申请人提供）：该项目的目标是通过访问化学多样性空间区域来组装一系列中试规模的杂环文库，从而发现新的生物活性化学型，这些区域在PubChem数据库中没有表示，在NIH分子文库小分子库（MLSMR）中也没有。此类文库的设计将以三个主要考虑因素为指导，包括(a)密切相关的化学型的生物活性验证；(b)有利的物理化学性质的严格计算分析；(c)开发简洁、平行的合成协议，以实现母库的高效组装、活性化合物的补充和重点库的构建。该项目分为四个具体目标，包括(a)建立基于二氢喹诺酮类药物和类西芹类药物的文库；(b)支架多样化吡咯烷酮文库的组装；(c)合成三环苯二氮卓类化合物库；(d)基于多环氨基胍的文库组装。我们将准备7个杂环文库（3600个新化合物），旨在用复杂的天然产物样化合物扩展MLSMR集合，以便鉴定具有不同生物功能的新小分子调节剂。

DESCRIPTION (provided by applicant): The objective of this project is to assemble a series of pilot-scale heterocyclic libraries to enable the discovery of new bioactive chemotypes by accessing the regions of chemical diversity space, which are not represented in the PubChem database and absent in the NIH Molecular Libraries Small-Molecule Repository (MLSMR). The design of such libraries will be guided by three main considerations, including (a) validated biological activity of closely related chemotypes; (b) rigorous computational analysis of favorable physicochemical properties; and (c) development of concise, parallel synthetic protocols to enable efficient assembly of parent libraries, resupply of active compounds and construction of focused libraries. The project is divided into four specific aims, including (a) construction of libraries based on dihydroquinolone and quassinoids; (b) assembly of scaffold-diversified pyrrolidinone libraries; (c) synthesis of tricyclic benzodiazepine-fused library; and (d) assembly of polycyclic amino guanidine-based libraries. We will prepare seven heterocyclic libraries (3,600 new compounds), which are designed to expand the MLSMR collection with sophisticated, natural product-like compounds in order to enable identification of new small- molecule modulators of diverse biological functions. PUBLIC HEALTH RELEVANCE: The objective of this project is to assemble a series of chemical libraries which are not represented in the PubChem database and absent in the NIH Molecular Libraries Small-Molecule Repository. Subsequent high-throughput biological screening of such compound libraries will produce new chemical tools, large amount of publicly accessible information, and will facilitate basic biomedical research and development of new therapeutic agents.