4UH7: Structure Of Bovine Endothelial Nitric Oxide Synthase Heme Domain In Complex With N1-(3-(2-(6-amino-4-methylpyridin-2- Yl)ethyl)phenyl)-n1,n2-dimethylethane-1,2-diamine

Citation:
Abstract
We have analyzed a recently obtained crystal structure of human neuronal nitric oxide synthase (nNOS) and then designed and synthesized several 2-aminopyridine derivatives containing a truncated side chain to avoid the hydrophobic pocket that differentiates human and rat nNOS in an attempt to explore alternative binding poses along the substrate access channel of human nNOS. Introduction of an N-methylethane-1,2-diamine side chain and conformational constraints such as benzonitrile and pyridine as the middle aromatic linker were sufficient to increase human and rat nNOS binding affinity and inducible and endothelial NOS selectivity. We found that 14b is a potent inhibitor; the binding modes with human and rat nNOS are unexpected, inducing side chain rotamer changes in Gln478 (rat) at the top of the active site. Compound 19c exhibits Ki values of 24 and 55 nM for rat and human nNOS, respectively, with 153-fold iNOS and 1040-fold eNOS selectivity. 19c has 18% oral bioavailability.
PDB ID: 4UH7Download
MMDB ID: 130873
PDB Deposition Date: 2015/3/23
Updated in MMDB: 2015/08
Experimental Method:
x-ray diffraction
Resolution: 2.24  Å
Source Organism:
Similar Structures:
Biological Unit for 4UH7: dimeric; determined by author and by software (PISA)
Molecular Components in 4UH7
Label Count Molecule
Proteins (2 molecules)
2
Nitric Oxide Synthase, Endothelial(Gene symbol: NOS3)
Molecule annotation
Chemicals (14 molecules)
1
2
2
2
3
3
4
4
5
2
6
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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