4D38: Structure Of Bovine Endothelial Nitric Oxide Synthase Heme Domain In Complex With (1r,2r)-2-(3-fluorobenzyl)-n-{2-[2- (1h-imidazol-1-yl)pyrimidin-4-yl]ethyl}cyclopropanamine

Citation:
Abstract
Selective inhibition of neuronal nitric oxide synthase (nNOS) is an important therapeutic approach to target neurodegenerative disorders. However, the majority of the nNOS inhibitors developed are arginine mimetics and, therefore, suffer from poor bioavailability. We designed a novel strategy to combine a more pharmacokinetically favorable 2-imidazolylpyrimidine head with promising structural components from previous inhibitors. In conjunction with extensive structure-activity studies, several highly potent and selective inhibitors of nNOS were discovered. X-ray crystallographic analysis reveals that these type II inhibitors utilize the same hydrophobic pocket to gain strong inhibitory potency (13), as well as high isoform selectivity. Interestingly, select compounds from this series (9) showed good permeability and low efflux in a Caco-2 assay, suggesting potential oral bioavailability, and exhibited minimal off-target binding to 50 central nervous system receptors. Furthermore, even with heme-coordinating groups in the molecule, modifying other pharmacophoric fragments minimized undesirable inhibition of cytochrome P450s from human liver microsomes.
PDB ID: 4D38Download
MMDB ID: 127571
PDB Deposition Date: 2014/10/20
Updated in MMDB: 2016/05
Experimental Method:
x-ray diffraction
Resolution: 2.3  Å
Source Organism:
Similar Structures:
Biological Unit for 4D38: dimeric; determined by author and by software (PISA)
Molecular Components in 4D38
Label Count Molecule
Proteins (2 molecules)
2
Nitric Oxide Synthase, Endothelial(Gene symbol: NOS3)
Molecule annotation
Chemicals (11 molecules)
1
2
2
2
3
2
4
2
5
2
6
1
* Click molecule labels to explore molecular sequence information.

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