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，一种公认的信使分子 在神经、内皮和免疫系统中。 高浓度的硝酸盐 氧化物，然而，负责中毒性休克，心脏病， 脑损伤 因此，抑制这种酶已成为一种 主要药物靶点 尽管内皮细胞、神经细胞和 可诱导同种型是高度同源的，它们在几个方面不同 方面，并已被证明有不同的活性位点， 抑制研究。 血红素结构域的最新晶体学研究进展 内皮和诱导型亚型显示了强的保守性， 活性位点残基。 我们实验室目前的工作利用核磁共振 弛豫方法和衬底晶体结构解释 这些酶的特异性和抑制谱。 计算机 图形实验室资源，包括MidasPlus，用于 晶体结构的可视化和建模， 抑制剂复合物对异构体选择性的合理设计 抑制剂的

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.