Bacillus anthracis, the cause of Anthrax, poses a considerable danger because of its potential use in bioterrorism. Respiratory anthrax infections are almost invariably fatal despite antibiotic treatment. Existing vaccines provide no protection against certain strains of B. anthracis. A small drug-like molecule that could inhibit the action of lethal factor, the zinc metalloprotease responsible for the lethal effects of bacillus anthracis, could provide significant protection against anthrax. Using patented and proprietary protein structure-based methods, Structural Bioinformatics Inc. extracted 3D-pharmacophore information from the computationally modeled LF substrate MAPKK1 during Phase I. After synthesis based on this pharmacophore, seven compounds with 1C50 <50 mu M were obtained, including one with 1C50 = 2.7 mu M. The goal of Phase Il is to identify noncytotoxic LF inhibitors that inhibit the ability of anthrax dual toxin (LF + anthrax protective antigen) to kill monocytic cells, with IC50 < 100 nM, and >100-fold selectivity against LF versus human metalloenzymes. To this end, refined pharmacophores and docking models will be developed by applying SBl's technology to crystal structures data for LF and LF/inhibitor complexes. The long-term goal of this project is to develop a clinically useful small molecule that blocks the toxic effects of bacillus anthracis.