4CAR: Structure Of Bovine Endothelial Nitric Oxide Synthase Heme Domain In Complex With 7-((3-fluorophenethylamino)methyl) Quinolin-2-amine

Citation:
Abstract
Since high levels of nitric oxide (NO) are implicated in neurodegenerative disorders, inhibition of the neuronal isoform of nitric oxide synthase (nNOS) and reduction of NO levels are therapeutically desirable. Nonetheless, many nNOS inhibitors mimic l-arginine and are poorly bioavailable. 2-Aminoquinoline-based scaffolds were designed with the hope that they could (a) mimic aminopyridines as potent, isoform-selective arginine isosteres and (b) possess chemical properties more conducive to oral bioavailability and CNS penetration. A series of these compounds was synthesized and assayed against purified nNOS enzymes, endothelial NOS (eNOS), and inducible NOS (iNOS). Several compounds built on a 7-substituted 2-aminoquinoline core are potent and isoform-selective; X-ray crystallography indicates that aminoquinolines exert inhibitory effects by mimicking substrate interactions with the conserved active site glutamate residue. The most potent and selective compounds, 7 and 15, were tested in a Caco-2 assay and showed good permeability and low efflux, suggesting high potential for oral bioavailability.
PDB ID: 4CARDownload
MMDB ID: 117600
PDB Deposition Date: 2013/10/8
Updated in MMDB: 2014/03
Experimental Method:
x-ray diffraction
Resolution: 2.05  Å
Source Organism:
Similar Structures:
Biological Unit for 4CAR: dimeric; determined by author and by software (PISA)
Molecular Components in 4CAR
Label Count Molecule
Proteins (2 molecules)
2
Nitric Oxide Synthase, Endothelial(Gene symbol: NOS3)
Molecule annotation
Chemicals (13 molecules)
1
2
2
2
3
2
4
4
5
2
6
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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