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          Institute: MPI für medizinische Forschung     Collection: Abteilung Biomolekulare Mechanismen     Display Documents



ID: 273189.0, MPI für medizinische Forschung / Abteilung Biomolekulare Mechanismen
Structural Analysis of Isoform−Specific Inhibitors Targeting the Tetrahydrobiopterin Binding Site of Human Nitric Oxide Synthases
Translation of Title:Structural Analysis of Isoform−Specific Inhibitors Targeting the Tetrahydrobiopterin Binding Site of Human Nitric Oxide Synthases
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.
Language:English
Date of Publication (YYYY-MM-DD):2005-01-01
Title of Journal:Journal of Medicinal Chemistry
Journal Abbrev.:J. Med. Chem.
Volume:48
Issue / Number:15
Start Page:4783
End Page:4792
Copyright:American Chemical Society
Review Status:Peer-review
Audience:Experts Only
Intended Educational Use:No
Abstract / Description: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.
Last Change of the Resource (YYYY-MM-DD):--
External Publication Status:published
Document Type:Article
Communicated by:Wulf Kaiser
Affiliations:MPI für medizinische Forschung/Abteilung Biomolekulare Mechanismen
Identifiers:LOCALID:6572
URI:http://pubs.acs.org/cgi-bin/article.cgi/jmcmar/200...
URI:http://pubs.acs.org/cgi-bin/article.cgi/jmcmar/200...
URI:http://pubs.acs.org/cgi-bin/abstract.cgi/jmcmar/20...
DOI:10.1021/jm050007x S0022-2623(05)00007-5
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