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J. Biol. Chem., Vol. 276, Issue 52, 49133-49141, December 28, 2001

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Structural Basis for Pterin Antagonism in Nitric-oxide Synthase
DEVELOPMENT OF NOVEL 4-OXO-PTERIDINE ANTAGONISTS OF (6R)-5,6,7,8-TETRAHYDROBIOPTERIN^*

Peter Kotsonis, Lothar G. Fröhlich, C. S. Raman^§, Huiying Li^¶, Michael Berg, Rainer Gerwig, Viola Groehn, Yonghan Kang, Najim Al-Masoudi, Shahriyar Taghavi-Moghadam, Detlev Mohr, Ursula Münch, Joachim Schnabel, Pavel Martásek^**, Bettie S. S. Masters^**, Hartmut Strobel, Thomas Poulos^¶, Hans Matter, Wolfgang Pfleiderer, and Harald H. H. W. Schmidt^§§

From the Department of Pharmacology and Toxicology, Julius-Maximilians University, Versbacher Straße 9, Würzburg 97078, Germany, the ^§ Structural Biology Center MSB 6.128, Department of Biochemistry and Molecular Biology, University of Texas Medical School, Houston, Texas 77030, the ^¶ Department of Molecular Biology and Biochemistry, Program in Macromolecular Structure, University of California, Irvine, California 92697, the  Faculty of Chemistry, University of Konstanz, Konstanz 78434, Germany, the ^** Department of Biochemistry, University of Texas Health Science Center, San Antonio, Texas 78229, and  Aventis Pharma, Research Chemistry Frankfurt, Building G838, Frankfurt 65926, Germany

Pathological nitric oxide (NO) generation in sepsis, inflammation, and stroke may be therapeutically controlled by inhibiting NO synthases (NOS). Here we targeted the (6R)-5,6,7,8-tetrahydro-L-biopterin (H₄Bip)-binding site of NOS, which, upon cofactor binding, maximally increases enzyme activity and NO production from substrate L-arginine. The first generation of H₄Bip-based NOS inhibitors employed a 4-amino pharmacophore of H₄Bip analogous to antifolates such as methotrexate. We developed a novel series of 4-oxo-pteridine derivatives that were screened for inhibition against neuronal NOS (NOS-I) and a structure-activity relationship was determined. To understand the structural basis for pterin antagonism, selected derivatives were docked into the NOS pterin binding cavity. Using a reduced 4-oxo-pteridine scaffold, derivatives with certain modifications such as electron-rich aromatic phenyl or benzoyl groups at the 5- and 6-positions, were discovered to markedly inhibit NOS-I, possibly due to hydrophobic and electrostatic interactions with Phe⁴⁶² and Ser¹⁰⁴, respectively, within the pterin binding pocket. One of the most effective 4-oxo compounds and, for comparisons an active 4-amino derivative, were then co-crystallized with the endothelial NOS (NOS-III) oxygenase domain and this structure solved to confirm the hypothetical binding modes. Collectively, these findings suggest (i) that, unlike the antifolate principle, the 4-amino substituent is not essential for developing pterin-based NOS inhibitors and (ii), provide a steric and electrostatic basis for their rational design.

The atomic coordinates and structure factors (code 1DMJ) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

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