Departments of Molecular Biology & Biochemistry, Pharmaceutical Sciences, and Chemistry, University of California, Irvine, Irvine, CA 92697-3900, USA.
Departments of Molecular Biology & Biochemistry, Pharmaceutical Sciences, and Chemistry, University of California, Irvine, Irvine, CA 92697-3900, USA.
Nitric Oxide. 2017 Feb 28;63:68-77. doi: 10.1016/j.niox.2016.11.004. Epub 2016 Nov 23.
Once it was discovered that the enzyme nitric oxide synthase (NOS) is responsible for the biosynthesis of NO, NOS became a drug target. Particularly important is the over production of NO by neuronal NOS (nNOS) in various neurodegenerative disorders. After the various NOS isoforms were identified, inhibitor development proceeded rapidly. It soon became evident, however, that isoform selectivity presents a major challenge. All 3 human NOS isoforms, nNOS, eNOS (endothelial NOS), and iNOS (inducible NOS) have nearly identical active site structures thus making selective inhibitor design especially difficult. Of particular importance is the avoidance of inhibiting eNOS owing to its vital role in the cardiovascular system. This review summarizes some of the history of NOS inhibitor development and more recent advances in developing isoform selective inhibitors using primarily structure-based approaches.
一旦发现酶一氧化氮合酶（NOS）负责 NO 的生物合成，NOS 就成为了药物靶点。特别重要的是，神经元 NOS（nNOS）在各种神经退行性疾病中产生过多的 NO。在确定了各种 NOS 同工型之后，抑制剂的开发迅速推进。然而，很快就明显看出，同工型选择性是一个主要挑战。所有 3 种人类 NOS 同工型，nNOS、eNOS（内皮 NOS）和 iNOS（诱导型 NOS）的活性部位结构几乎相同，因此使得选择性抑制剂的设计特别困难。特别重要的是避免抑制 eNOS，因为它在心血管系统中起着至关重要的作用。本综述总结了 NOS 抑制剂开发的一些历史，以及最近在使用主要基于结构的方法开发同工型选择性抑制剂方面的进展。
