application): This is a proposal to develop inhibitors of the lethal factor (LF) zinc protease that is responsible for the deadly effects of Anthrax. The Structural Bioinformatics group intend to use homology modeling and Monte Carlo simulations to develop structural models and consensus sequences for peptides that are known to be cleaved by the lethal factor. They will then use other computational techniques to select hydroxamates from a virtual library as potential inhibitors. Approximately 40 compounds will be prepared, and tested for their ability to inhibit LF. The significant milestone proposed for Phase I is to find an LF inhibitor with a Ki <1 uM; that would be 300 times better than the best inhibitor cited in this proposal (which is also a hydroxamate)
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