4UPQ

Structure of bovine endothelial nitric oxide synthase heme domain in complex with N',N'-{[(2R)-3-aminopropane-1,2-diyl]bis(oxymethanediylbenzene-3,1-diyl)}dithiophene-2-carboximidamide

Summary for 4UPQ

• Entry DOI: 10.2210/pdb4upq/pdb
• Related: 4UPM 4UPN 4UPO 4UPP 4UPR 4UPS 4UPT
• Descriptor: NITRIC OXIDE SYNTHASE, ENDOTHELIAL, PROTOPORPHYRIN IX CONTAINING FE, 5,6,7,8-TETRAHYDROBIOPTERIN, ... (8 entities in total)
• Functional Keywords: oxidoreductase, inhibitor complex
• Biological source: BOS TAURUS (CATTLE)
• Cellular location: Cell membrane: P29473
• Total number of polymer chains: 2
• Total formula weight: 102694.63

Authors

Li, H.,Poulos, T.L. (deposition date: 2014-06-17, release date: 2014-08-20, Last modification date: 2014-09-24)

Primary citation

Jing, Q.,Li, H.,Roman, L.J.,Martasek, P.,Poulos, T.L.,Silverman, R.B.
Combination of Chiral Linkers with Thiophenecarboximidamide Heads to Improve the Selectivity of Inhibitors of Neuronal Nitric Oxide Synthase.
Bioorg.Med.Chem.Lett., 24:4504-, 2014

PubMed 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 14.7 nM 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.

PubMed: 25149509
DOI: 10.1016/J.BMCL.2014.07.079

Experimental method

X-RAY DIFFRACTION (2.03 Å)