5ADA: Structure Of Rat Neuronal Nitric Oxide Synthase Heme Domain In Complex With 7-(((3-((dimethylamino)methyl)phenyl) Amino)methyl)quinolin-2-amine

Citation:
Abstract
Excess nitric oxide (NO) produced by neuronal nitric oxide synthase (nNOS) is implicated in neurodegenerative disorders. As a result, inhibition of nNOS and reduction of NO levels is desirable therapeutically, but many nNOS inhibitors are poorly bioavailable. Promising members of our previously reported 2-aminoquinoline class of nNOS inhibitors, although orally bioavailable and brain-penetrant, suffer from unfavorable off-target binding to other CNS receptors, and they resemble known promiscuous binders. Rearranged phenyl ether- and aniline-linked 2-aminoquinoline derivatives were therefore designed to (a) disrupt the promiscuous binding pharmacophore and diminish off-target interactions and (b) preserve potency, isoform selectivity, and cell permeability. A series of these compounds was synthesized and tested against purified nNOS, endothelial NOS (eNOS), and inducible NOS (iNOS) enzymes. One compound, 20, displayed high potency, selectivity, and good human nNOS inhibition, and retained some permeability in a Caco-2 assay. Most promisingly, CNS receptor counterscreening revealed that this rearranged scaffold significantly reduces off-target binding.
PDB ID: 5ADADownload
MMDB ID: 133684
PDB Deposition Date: 2015/8/20
Updated in MMDB: 2015/11
Experimental Method:
x-ray diffraction
Resolution: 1.98  Å
Source Organism:
Similar Structures:
Biological Unit for 5ADA: dimeric; determined by author and by software (PISA)
Molecular Components in 5ADA
Label Count Molecule
Proteins (2 molecules)
2
Nitric Oxide Synthase, Brain(Gene symbol: Nos1)
Molecule annotation
Chemicals (9 molecules)
1
2
2
2
3
2
4
2
5
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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