Funding is requested for a Bruker Avance III 700 MHz NMR spectrometer equipped with a cryogenic probe and Tecan robot for fully automated compound library screening to support the biomedical research of a consortium of investigators. NMR-based screening is extremely versatile: applicable to a wide range of targets and compound libraries as well as ligand binding affinities. As such it has made an important impact on drug discovery and progressing new medicines into the clinic. NMR screening complements traditional high-throughput screening technologies allowing for hit validation and optimization (providing structural information on the mode of binding). The requested instrument will have an immediate impact on the biomedical research of the participating faculty from Dartmouth College, Dartmouth Medical School and the Norris Cotton Cancer Center and regional universities including University of Vermont Medical School, University of Massachusetts, University of Montreal, and University of Connecticut Health Science Center. Projects include inhibition of key protein-protein interactions in important signal transduction cascades, screening for competitive and allosteric enzyme inhibitors, and structural insight for rational modification of natural products. The instrument will form the basis of a screening facility to be housed in a new life sciences building under construction on the Dartmouth campus. Additional support of this facility includes that salary of an NMR technician as well as the recent recruitment of two research scientists: one with over 8 years of industrial experience in the utilization of NMR in library screening and a second with expertise in synthetic chemistry for elaboration of hits or tethering of optimized fragments. With this expertise available, the facility will be readily accessible to the biomedical researcher with little screening or NMR experience. Oversight of the facility operation will be guaranteed by an advisory committee of three of the primary users. An external advisory committee of leading experts in NMR screening has been formed to assist in optimal utilization of the facility and application of developing technologies.
The requested instrument and screening facility will provide vital data to translate fundamental biochemical discoveries into lead candidates for molecular intervention for cancer, cystic fibrosis, inflammation, osteoporosis, and drug addiction.
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