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  Structural analysis of isoform-specific inhibitors targeting the tetrahydrobiopterin binding site of human nitric oxide synthases

Matter, H., Kumar, H. S. A., Fedorov, R., Frey, A., Kotsonis, P., Hartmann, E., et al. (2005). Structural analysis of isoform-specific inhibitors targeting the tetrahydrobiopterin binding site of human nitric oxide synthases. Journal of Medicinal Chemistry, 48(15), 4783-4792. doi:10.1021/jm050007x.

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JMedicinChem_48_2005_4783.pdf (Any fulltext), 509KB
 
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 Creators:
Matter, Hans, Author
Kumar, H. S. Arun, Author
Fedorov, Roman1, Author              
Frey, Armin, Author
Kotsonis, Peter, Author
Hartmann, Elisabeth1, Author              
Fröhlich, Lothar G., Author
Reif, Andreas, Author
Pfleiderer, Wolfgang, Author
Scheurer, Peter, Author
Ghosh, Dipak K., Author
Schlichting, Ilme1, Author              
Schmidt, Harald H. H. W., Author
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1Department of Biomolecular Mechanisms, Max Planck Institute for Medical Research, Max Planck Society, ou_1497700              

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 Abstract: 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 (H(4)Bip) 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 H(4)Bip 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 H(4)Bip binding site with enhanced isoform selectivity for therapeutics in pathology with NO overproduction.

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Language(s): eng - English
 Dates: 2005-01-052005-06-252005-07-28
 Publication Status: Published in print
 Pages: 10
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 Rev. Type: Peer
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Title: Journal of Medicinal Chemistry
Source Genre: Journal
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Publ. Info: Washington DC : ACS Publications
Pages: - Volume / Issue: 48 (15) Sequence Number: - Start / End Page: 4783 - 4792 Identifier: ISSN: 0022-2623
CoNE: https://pure.mpg.de/cone/journals/resource/110992357271168