Structural Analysis of Isoform-Specific Inhibitors Targeting the Tetrahydrobiopterin Binding Site of Human Nitric Oxide Synthases

Nitric oxide synthesized from l-arginine by nitric oxide synthase isoforms (NOS-I−III) is physiologically important but also can be deleterious when overproduced. Selective NOS inhibitors are of clinical interest, given their differing pathophysiological roles. Here we describe our approach to targe...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2005-07, Vol.48 (15), p.4783-4792
Main Authors: Matter, Hans, Kumar, H. S. Arun, Fedorov, Roman, Frey, Armin, Kotsonis, Peter, Hartmann, Elisabeth, Fröhlich, Lothar G, Reif, Andreas, Pfleiderer, Wolfgang, Scheurer, Peter, Ghosh, Dipak K, Schlichting, Ilme, Schmidt, Harald H. H. W
Format: Article
Language:English
Subjects:
Analytical, structural and metabolic biochemistry
Animals
Binding Sites
Biological and medical sciences
Biopterins - analogs & derivatives
Biopterins - chemistry
Crystallography, X-Ray
Enzymes and enzyme inhibitors
Fundamental and applied biological sciences. Psychology
Humans
Isoenzymes - antagonists & inhibitors
Isoenzymes - chemistry
Ligands
Medical sciences
Miscellaneous
Models, Molecular
Molecular Structure
Nerve Tissue Proteins - chemistry
Nitric Oxide Synthase - antagonists & inhibitors
Nitric Oxide Synthase - chemistry
Nitric Oxide Synthase Type I
Nitric Oxide Synthase Type II
Nitric Oxide Synthase Type III
Oxidoreductases
Pharmacology. Drug treatments
Protein Structure, Tertiary
Pteridines - chemical synthesis
Pteridines - chemistry
Rats
Structure-Activity Relationship
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Summary:Nitric oxide synthesized from l-arginine by nitric oxide synthase isoforms (NOS-I−III) is physiologically important but also can be deleterious when overproduced. Selective NOS inhibitors are of clinical interest, given their differing pathophysiological roles. Here we describe our approach to target the unique NOS (6R,1‘R,2‘S)-5,6,7,8-tetrahydrobiopterin (H4Bip) binding site. By a combination of ligand- and structure-based design, the structure−activity relationship (SAR) for a focused set of 41 pteridine analogues on four scaffolds was developed, revealing selective NOS-I inhibitors. The X-ray crystal structure of rat NOS-I dimeric-oxygenase domain with H4Bip and l-arginine was determined and used for human isoform homology modeling. All available NOS structural information was subjected to comparative analysis of favorable protein−ligand interactions using the GRID/concensus principal component analysis (CPCA) approach to identify the isoform-specific interaction site. Our interpretation, based on protein structures, is in good agreement with the ligand SAR and thus permits the rational design of next-generation inhibitors targeting the H4Bip binding site with enhanced isoform selectivity for therapeutics in pathology with NO overproduction.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm050007x