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.