4KCM: Structure of neuronal nitric oxide synthase heme domain in complex with N-(4-(2-(ethyl(3-(thiophene-2-carboximidamido)benzyl)amino)ethyl)phenyl)thiophene-2-carboximidamide

Citation:
Abstract
Selective inhibitors of neuronal nitric oxide synthase (nNOS) are regarded as valuable and powerful agents with therapeutic potential for the treatment of chronic neurodegenerative pathologies and human melanoma. Here, we describe a novel hybrid strategy that combines the pharmacokinetically promising thiophene-2-carboximidamide fragment and structural features of our previously reported potent and selective aminopyridine inhibitors. Two inhibitors, 13 and 14, show low nanomolar inhibitory potency (Ki = 5 nM for nNOS) and good isoform selectivities (nNOS over eNOS [440- and 540-fold, respectively] and over iNOS [260- and 340-fold, respectively]). The crystal structures of these nNOS-inhibitor complexes reveal a new hot spot that explains the selectivity of 14 and why converting the secondary to tertiary amine leads to enhanced selectivity. More importantly, these compounds are the first highly potent and selective nNOS inhibitory agents that exhibit excellent in vitro efficacy in melanoma cell lines.
PDB ID: 4KCMDownload
MMDB ID: 117446
PDB Deposition Date: 2013/4/24
Updated in MMDB: 2017/11
Experimental Method:
x-ray diffraction
Resolution: 2.074  Å
Source Organism:
Similar Structures:
Biological Unit for 4KCM: dimeric; determined by author and by software (PISA)
Molecular Components in 4KCM
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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