DESIGNING ISOFORM SELECTIVE INHIBITORS OF NOS

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Nitric Oxide Synthase converts arginine to citrulline and the radical diatomic nitric oxide, a well established messenger molecule in the neural, endothelial and immune systems. High levels of nitric oxide, however, are responsible for toxic shock, cardiac disease and brain damage. Inhibition of this enzyme has therefore become a primary pharmaceutical target. Although the endothelial, neuronal and induceable isoforms are highly homologous they differ in several aspects and have been shown to have different active sites by inhibition studies. Recent crystallography of the heme domain of the endothelial and inducible isoforms shows strong conservation of the active site residues. Current work in our laboratory utilizes NMR relaxation methods and the crystal structure to explain the substrate specificity and inhibition profiles of these enzymes. Computer Graphics Laboratory resources, including MidasPlus, are used for visualization and modeling of the crystallographic structure and inhibitor complexes towards the rational design of isoform selective inhibitors.