The successful completion of the Human Genome Project has provided an enormous wealth of biological information and identified an abundance of potential new drug targets. A critical component of realizing the promise of genomics efforts is access to chemical compounds that modulate the activities of specific gene products in a desired manner. These compounds can be used as discovery tools to interrogate cellular pathways in greater depth, and as chemical leads for validating or invalidating disease-relevant targets in attempts to devise new therapeutics. The significance of building a """"""""toolbox"""""""" of chemical probes for exploring components of cellular pathways in health and disease will be immense. Achieving this ultimate goal represents a considerable challenge that requires a multidisciplinary and highly coordinated effort. We propose to form a Molecular Libraries Screening Center in San Diego, as a national resource to speed the discovery of small-molecule chemicals for use as research tools. The Center will build upon the significant resources already established at the lead institution for this collaborative endeavor (The Burnham Institute) and at participating neighboring San Diego area institutions, and it will involve substantial instrumentation support from a corporate co-development partner, resulting in throughput capabilities within the first year approaching one million assay wells per day. While the Center will have expertise in several high-throughput screening (HTS) platforms, we will emphasize two technological themes that will enhance and complement the overall capabilities of the Screening Center Network. First, the San Diego Chemical Library Screening Center will have special expertise in high-throughput microscopy as a tool for performing high-content, cell-based screens where cellular phenotypes drive compound selection in an unbiased manner. Second, the Center will emphasize NMR-based small-molecule discovery and optimization as an additional strategy. NMR-based methods are exceptionally valuable when tackling molecular targets that are not easily tractable, such as protein-protein interactions and protein targets that cannot be formatted for the classical HTS environment. For HTS assay development, our plan focuses on a biological (rather than technical) theme of apoptosis and cell death regulation, providing a cohesive biological context for small-molecule discovery during the build-up phase of the Center, and serving as a rapid way to generate proof-of-concept data by tapping into a wealth of domain-specific expertise and an abundance of unique reagents that facilitate rapid HTS assay development and post-screening evaluation of compounds. A secondary theme of cell differentiation will also be emphasized. Both of these biological themes nicely complement the technological themes within the Center. Altogether, the contributions of the proposed Center will provide technology platforms and chemical probes that address a wide range of biological disciplines, and that empower the scientific research community supported by NIH to integrate chemistry and chemical biology into their discovery research endeavors.
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