Biology and chemistry of the inhibition of nitric oxide synthases by pteridine-derivatives as therapeutic agents.
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.
Matter
Hans
H
Aventis Pharma Deutschland GmbH, DI&A Chemistry, Molecular Modelling, Building G 878, D-65926, Frankfurt am Main, Germany. hans.matter@aventis.com
Kotsonis
Peter
P
D000818:Animals; D001120:Arginine / Q000378:metabolism; D001665:Binding Sites; D001708:Biopterins / Q000031:analogs & derivatives* / Q000502:physiology; D002545:Brain Ischemia / Q000188:drug therapy / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000201:enzymology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000201:enzymology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000502:physiology; D011487:Protein Conformation; D011621:Pteridines / Q000737:chemistry* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D018805:Sepsis / Q000188:drug therapy / Q000201:enzymology; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D007527:Isoenzymes; D011621:Pteridines; D001708:Biopterins; D001120:Arginine; D019001:Nitric Oxide Synthase; C003402:sapropterin