? The overall goal of this proposal is to develop a high throughput method that can be used to assess the potential for covalent binding in early stage drug development. This novel method will allow for the determination of toxicological profiles quickly and cheaply. Currently, the identification of covalent intermediates typically requires a radiolabeled compound or an antibody to the labeled protein. These methods are tedious and are not easily amenable to high throughput screening. More recently, covalent adducts have been characterize by mass spectrometric methods. The method we propose herein employs similar tools, such as mass spectrometry, but adduct characterization should be much more rapid since the same (or a small number) of peptide fragments would be analyzed for all compounds. The efforts outlined in this proposal, if successful, could serve to significantly impact the way in which drugs are developed under the current approach. The reduction in the time required to bring drugs to market can have a significant social and economic impact by helping drug companies meet the steeply increasing demands of an aging, and more health-care intensive population in a cost effective way. With safety and toxicity issues currently usurping the largest portion of time and money requirements for new drug development, this proposal aims to significantly improve the efficiency of new drug development and the current level of healthcare in this country. ? ?
