Matter Hans, Kotsonis Peter
Aventis Pharma Deutschland GmbH, DI&A Chemistry, Molecular Modelling, Building G 878, D-65926, Frankfurt am Main, Germany.
Med Res Rev. 2004 Sep;24(5):662-84. doi: 10.1002/med.20005.
Inhibitors of the family of nitric oxide synthases (NOS-I-III; EC 1.14.13.39) are of interest as pharmacological agents to modulate pathologically high nitric oxide (NO) levels in inflammation, sepsis, and stroke. In this article, we discuss the approach for targeting the unique (6R)-5,6,7,8-tetrahydro-L-biopterin (H4Bip) binding site of NOS by appropriate inhibitors. This binding site maximally increases enzyme activity and NO production from the substrate L-arginine upon cofactor binding. The first generation of H4Bip-based NOS inhibitors was based on 4-amino H4Bip derivatives in analogy to anti-folates such as methotrexate. In addition, we discuss the structure-activity relationship of a related series of 4-oxo-pteridine derivatives. Furthermore, molecular modeling studies provide an understanding of pterin antagonism on a structural level based on favorable and unfavorable interactions between protein binding site and ligands. These techniques include 3D-QSAR (CoMFA, CoMSIA) to understand ligand affinity and GRID/consensus principal component analysis (CPCA) to learn about selectivity requirements. Collectively these approaches, in combination with the presented SAR and structural data, provide useful information for the design of novel NOS inhibitors with increased isoform selectivity.
一氧化氮合酶家族（NOS-I-III；EC 1.14.13.39）的抑制剂作为一种药理剂，可调节炎症、败血症和中风中病理性升高的一氧化氮（NO）水平，因而备受关注。在本文中，我们讨论了通过合适的抑制剂靶向一氧化氮合酶独特的（6R）-5,6,7,8-四氢-L-生物蝶呤（H4Bip）结合位点的方法。该结合位点在辅因子结合后可最大程度地提高酶活性以及底物L-精氨酸生成NO的量。第一代基于H4Bip的一氧化氮合酶抑制剂是基于4-氨基H4Bip衍生物，类似于甲氨蝶呤等抗叶酸剂。此外，我们还讨论了一系列相关的4-氧代蝶啶衍生物的构效关系。此外，分子建模研究基于蛋白质结合位点与配体之间的有利和不利相互作用，从结构层面上提供了对蝶呤拮抗作用的理解。这些技术包括用于理解配体亲和力的3D-QSAR（比较分子场分析、比较分子相似性指数分析）以及用于了解选择性要求的GRID/共识主成分分析（CPCA）。这些方法与所呈现的构效关系和结构数据相结合，为设计具有更高亚型选择性的新型一氧化氮合酶抑制剂提供了有用信息。
