DESIGNING ISOFORM SELECTIVE INHIBITORS OF NOS

一氧化氮合酶将精氨酸转化为瓜氨酸 自由基双原子一氧化氮，一种成熟的信使分子 在神经、内皮和免疫系统中。高水平的硝酸盐 然而，氧化物是中毒性休克、心脏病和 脑部受损。因此，对这种酶的抑制已成为一种 主要药物目标。尽管血管内皮细胞、神经元和 可诱导的异构体高度同源，它们在几个方面不同 方面，并且已经被证明具有不同的活动站点 抑制研究。血红素结构域的最新结晶学研究 内皮细胞和诱导亚型显示出很强的保守性 活性中心残留物。我们实验室目前的工作是利用核磁共振 用弛豫方法和晶体结构解释衬底 这些酶的专一性和抑制率。电脑 图形实验室的资源，包括MidasPlus，用于 晶体结构和晶体结构的可视化和建模 阻滞剂复合体走向异构体选择性的合理设计 抑制剂。

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.