5FVQ: Structure Of Rat Neuronal Nitric Oxide Synthase Heme Domain In Complex With 4-methyl-6-(2-(5-(4-methylpiperazin-1-yl) Pyridin-3-yl)ethyl)pyridin-2-amine

Citation:
Abstract
Neuronal nitric oxide synthase (nNOS) is an important therapeutic target for the treatment of various neurodegenerative disorders. A major challenge in the design of nNOS inhibitors focuses on potency in humans and selectivity over other NOS isoforms. Here we report potent and selective human nNOS inhibitors based on the 2-aminopyridine scaffold with a central pyridine linker. Compound 14j, the most promising inhibitor in this study, exhibits excellent potency for rat nNOS (Ki = 16 nM) with 828-fold n/e and 118-fold n/i selectivity with a Ki value of 13 nM against human nNOS with 1761-fold human n/e selectivity. Compound 14j also displayed good metabolic stability in human liver microsomes, low plasma protein binding, and minimal binding to cytochromes P450 (CYPs), although it had little to no Caco-2 permeability.
PDB ID: 5FVQDownload
MMDB ID: 139427
PDB Deposition Date: 2016/2/10
Updated in MMDB: 2016/06
Experimental Method:
x-ray diffraction
Resolution: 1.95  Å
Source Organism:
Similar Structures:
Biological Unit for 5FVQ: dimeric; determined by author and by software (PISA)
Molecular Components in 5FVQ
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.

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