Expeditious, biologically driven Pilot Libraries for File Enhancement

用于文件增强的快速、生物驱动的试点库

• 批准号: 8119561
• 负责人: Christopher Hulme
• 金额: $ 37.56万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-05 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8119561
• 关键词: Address; Area; Binding; Biological; Biological Process; Biology; Chemicals; Chemistry; Collection; Critiques; Databases; Disease; Disease Progression; Drug Design; Evaluation; Family; Follow-Up Studies; Frequencies; Future; Genomics; Goals; Health; Human; Individual; Institutes; Libraries; Longevity; Measurement; Mediator of activation protein; Medical; Mind; Molecular; Molecular Bank; Molecular Probes; Online Systems; Output; Pattern; Pharmaceutical Chemistry; Pharmaceutical Preparations; Physiological; Preparation; Production; Property; Proteins; Protocols documentation; PubChem; Research Infrastructure; Research Personnel; Role; Route; Screening procedure; Solutions; Speed; System; Technology; Therapeutic; Time; Vendor; base; computerized tools; data sharing; design; improved; instrumentation; macromolecule; member; microwave electromagnetic radiation; molecular recognition; public health relevance; scaffold; skeletal; skills; small molecule; structural biology; tool

DESCRIPTION (provided by applicant): The aim of this application is to produce pilot-scale libraries for evaluation via the Molecular Library Screening Network (MLSCN). It is expected that the output from MLSCN screening of these "designer collections" will help enable the promise of chemical biology, unearthing quality small molecule probes to elucidate physiological roles of proteins of unknown function. 25 libraries will be targeted, comprising 25-80 characterized compounds (>10mg, >90% pure). To this end, effective file enhancement requires complementary skill sets in multiple functional areas and as such, the collective investigators have proposed a multitude of potentially robust medicinally relevant protocols and possess a depth of expertise in high-throughput medicinal chemistry and drug design principles spanning both academic and industrial settings. The combined infrastructures of the collaborative parties further strengthen this application, with ready access to state of the art screening, structural biology, high-throughput instrumentation and core chemistry facilities. The notion of scaffold uniqueness will be evaluated using measurements of molecular dissimilarity based on observed substructure patterns and their frequency of occurrence in PubChem and vendor databases. Evaluation tools will include but are not limited to standard diverse subset and hierarchical chemotype-based analyses. Selected scaffolds will also have a strong biological rational, often taking advantage of crucial molecular recognition motifs of multiple target families. All scaffolds are unique and viewed as structurally compelling. Resupply and future SAR studies will be facilitated by selection of scaffolds possessing 'High Iterative Efficiency Potential' that 1) improve the iterative speed of the medicinal chemist navigating the 'hypothesis-synthesis-screening' loop and 2) reduce the number of required iterations for milestone progression. Designer libraries detailed herein will be presenting opportunities for therapeutic advances in multiple indications.

描述（由申请人提供）：本申请的目的是生产通过分子库筛选网络（MLSCN）评估的试验级库。预计这些“设计器收集”的MLSCN筛选产量将有助于实现化学生物学的希望，发掘出质量的小分子探针，以阐明功能未知功能的蛋白质的生理作用。 25个文库将被靶向，包括25-80个特征化合物（> 10mg，> 90％纯）。为此，有效的文件增强需要在多个功能领域的互补技能集，因此，集体研究人员提出了多种潜在强大的药物相关方案，并具有高通量药物化学和药物设计原理的高度专业知识，以跨越学术和工业环境。协作各方的组合基础设施进一步加强了这一应用，并可以随时访问最先进的筛查，结构生物学，高通量仪器和核心化学设施。基于观察到的子结构模式及其在PubChem和供应商数据库中发生的频率，将评估支架唯一性的概念。评估工具将包括但不限于标准的不同子集和基于分层化学型的分析。选定的脚手架也将具有强大的生物学理性，通常会利用多个目标家族的关键分子识别基序。所有脚手架都是独一无二的，并被视为结构引人注目。通过选择具有“高迭代效率潜力”的脚手架的选择，将促进补给和未来的SAR研究，即1）提高药物化学家的迭代速度，从而导航“假设 - 合成筛查”循环和2）减少了里程碑进展所需的迭代次数。本文详细介绍的设计师图书馆将为多种迹象提供治疗进展的机会。