4UPM: Structure Of Rat Neuronal Nitric Oxide Synthase Heme Domain In Complex With N',n'-{[(2r)-3-aminopropane-1,2-diyl] Bis(oxymethanediylbenzene-3,1-diyl)}dithiophene-2-carboximidamide

Citation:
Abstract
To develop potent and selective nNOS inhibitors, a new series of double-headed molecules with chiral linkers that derive from natural amino acid derivatives have been designed and synthesized. The new structures integrate a thiophenecarboximidamide head with two types of chiral linkers, presenting easy synthesis and good inhibitory properties. Inhibitor (S)-9b exhibits a potency of 14.7nM against nNOS and is 1134 and 322-fold more selective for nNOS over eNOS and iNOS, respectively. Crystal structures show that the additional binding between the aminomethyl moiety of 9b and propionate A on the heme and tetrahydrobiopterin (H4B) in nNOS, but not eNOS, contributes to its high selectivity. This work demonstrates the advantage of integrating known structures into structure optimization, and it should be possible to more readily develop compounds that incorporate bioavailability with these advanced features. Moreover, this integrative strategy is a general approach in new drug discovery.
PDB ID: 4UPMDownload
MMDB ID: 122622
PDB Deposition Date: 2014/6/17
Updated in MMDB: 2014/10
Experimental Method:
x-ray diffraction
Resolution: 1.9  Å
Source Organism:
Similar Structures:
Biological Unit for 4UPM: dimeric; determined by author and by software (PISA)
Molecular Components in 4UPM
Label Count Molecule
Proteins (2 molecules)
2
Neuronal Nitric Oxide Synthase(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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