The Penn Center For Molecular Discovery

描述（由申请人提供）：拟议的分子图书馆筛选中心网络（MLSCN）“分子发现中心”汇集了来自宾夕法尼亚大学医学院、工程系和艺术与科学学院的跨学科团队。该中心将利用3个学院的14名核心教师的人才，并在统计学、HTS、并行合成和化学信息学领域得到9名领先的工业和学术顾问的支持。宾夕法尼亚大学分子发现中心的一个特别重点将包括(1)蛋白质水解酶的靶标，(2)涉及蛋白质组装/错误折叠和降解的生物学，以及(3)细胞内转录激活过程。蛋白酶约占大多数基因组的2%，对细胞内和细胞外的生理和病理过程至关重要。蛋白质组装/错误折叠和降解（淀粉样蛋白形成）是一类广泛的现象，对细胞生理学和病理学至关重要。转录调控是细胞内综合信号传导和细胞表型驱动因素的中心。将建立五个核心：检测实施、HTS、合成、信息学和管理。经过验证的命中，优先考虑探针优化将转移到合成核心。综合核心将采用三种不同的综合策略：基于结构的合理设计；构效关系驱动设计；以及利用金属配位体的快速组合聚焦探针扫描。这些核心将利用现有的和新的优势，在超小型化纳米升生化筛选，组合聚焦探针库合成和天然化合物多样化。所有核心都将由信息学核心支持。为了配合高通量化学生物学研究的任务，该中心将通过研究生水平的课程（药物发现和开发）和每年为期一天的暑期研讨会来增加教育机会。该项目响应了NIH路线图的目标，即应用已建立的HTS/合成方法和宾夕法尼亚大学开发的新兴下一代技术。

DESCRIPTION (provided by applicant): The proposed Molecular Libraries Screening Centers Network (MLSCN) "Center for Molecular Discovery" has assembled an interdisciplinary team from the Schools of Medicine, Engineering, and Arts & Sciences from the University of Pennsylvania. The Center will utilize the talents of 14 core faculty across 3 schools who are supported with 9 leading industrial and academic consultants in the areas of statistics, HTS, parallel synthesis, and cheminformatics. A special emphasis of the Penn Center for Molecular Discovery will include the targets of (1) proteolytic enzymes, (2) biology involving protein assembly/misfolding and degradation, and (3) intracellular processes of transcriptional activation. Proteases represent about 2% of most genomes and are critical to intracellular and extracellular physiologic and pathologic processes. Protein assembly/misfolding and degradation (amyloid formation) is a broad class of phenomenon critical to cellular physiology and pathology. Transcriptional regulation is at the center of integrative intracellular signaling and drivers of cellular phenotype. Five Cores will be established: Assay Implementation, HTS, Synthesis, Informatics, and Administration. Validated hits that are prioritized for probe optimization will be transferred to the Synthesis Core. The Synthesis Core will employ three distinct synthetic strategies: Structure-based rational design; Structure-activity relationship (SAR)-driven design; and rapid combinatorial focused probe scanning using metal-coordinated ligands. These Cores will employ existing and novel strengths in ultraminiaturized nanoliter biochemical screening, combinatorial focused probe library synthesis, and natural compound diversification. All Cores will be supported by the Informatics Core. In coordination with a mission of high throughput chemical-biology research, the Center will enhance educational opportunities through a graduate level course (Drug Discovery and Development) and a 1-day summer workshop during each year of the project. This project is responsive to the NIH Roadmap objectives to apply both establish HTS/Synthetic methods and emerging next generation technologies developed at the University of Pennsylvania.