Structural Studies on Nitric Oxide Synthase

项目描述：本项目的长期目标是研究一氧化氮合酶（NOS）的结构-功能关系，并开发亚型选择性NOS抑制剂和药物。NOS是负责NO生物合成的酶，NO是心血管和神经系统中至关重要的信号分子，也是免疫系统中的细胞毒性剂。哺乳动物有3种NOS亚型：eNOS（内皮NOS，调节血压）、nNOS（神经NOS，神经信号）和iNOS（诱导型NOS，免疫系统）。通过nNOS过度产生NO与许多神经退行性过程相关，因此，选择性阻断nNOS的药物应该具有相当大的治疗益处。选择性是重要的，因为目标是阻断nNOS而不是eNOS，因为eNOS在维持适当的血管张力和血压方面至关重要。这是一个具有挑战性的问题，因为所有3种NOS同工型的活性位点几乎相同，并且大多数公知的NOS抑制剂不是选择性的。使用晶体学，计算化学和药物化学的组合，nNOS选择性化合物已被开发，测试，并显示在动物模型中预防缺血性脑损伤非常有效。我们未来的目标是在这一初步工作的基础上进一步发展，并利用已发现的新的可药用靶点。关于结构-功能研究，未来的努力将集中在构象动力学的重要功能和解决通过生物信息学搜索新的基因组发现的新的NOS的结构。

DESCRIPTION (provided by applicant): The long range goal of this project is to study structure-function relationships in nitric oxide synthase (NOS) and to develop isoform selective NOS inhibitors and drugs. NOS is the enzyme responsible for the biosynthesis of NO, a critically important signaling molecule in the cardiovascular and nervous systems and also is a cytotoxic agents in the immune system. Mammals have 3 NOS isoforms: eNOS (endothelial NOS, regulates blood pressure), nNOS (neuronal NOS, neural signaling), and iNOS (inducible NOS, immune system). The over production of NO by nNOS is associated with a number of neuro-degenerative processes and thus, drugs that selectively block nNOS should be of considerable therapeutic benefit. Selectivity is important since the goal is to block nNOS but not eNOS since eNOS is critical in maintaining proper vascular tone and blood pressure. This is a challenging problem since the active site of all 3 NOS isoforms are nearly identical and a majority of well known NOS inhibitors are not selective. Using a combination of crystallography, computational chemistry, and medicinal chemistry nNOS-selective compounds have been developed, tested, and shown to be very effective in preventing ischemic brain damage in animal models. Our future goals are to further build on this initial work and to exploit new druggable target sites that have been discovered. With respect to structure-function studies, future efforts will focus on conformational dynamics important for function and solving the structure of novel NOSs discovered via bioinformatic searches of new genomes.