Download MendeleyStructural basis for pterin antagonism in nitric-oxide synthase. Development of novel 4-oxo-pteridine antagonists of (6R)-5,6,7,8-tetrahydrobiopterin
Kotsonis, P., Frohlich, L.G., Raman, C.S., Li, H., Berg, M., Gerwig, R., Groehn, V., Kang, Y., Al-Masoudi, N., Taghavi-Moghadam, S., Mohr, D., Munch, U., Schnabel, J., Martasek, P., Masters, B.S., Strobel, H., Poulos, T., Matter, H., Pfleiderer, W., Schmidt, H.H.(2001) J Biol Chem 276: 49133-49141
- PubMed: 11590164
- DOI: https://doi.org/10.1074/jbc.M011469200
- Primary Citation of Related Structures:
1DMJ, 1DMK - PubMed Abstract:
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 (H(4)Bip)-binding site of NOS, which, upon cofactor binding, maximally increases enzyme activity and NO production from substrate l-arginine. The first generation of H(4)Bip-based NOS inhibitors employed a 4-amino pharmacophore of H(4)Bip 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 Phe(462) and Ser(104), 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.
Organizational Affiliation:
Department of Pharmacology and Toxicology, Julius-Maximilians University, Versbacher Strasse 9, Würzburg 97078, Germany. [email protected]
