4KCO

Structure of neuronal nitric oxide synthase heme domain in complex with N-(3-((ethyl(3-fluorophenethyl)amino)methyl)phenyl)thiophene-2-carboximidamide

Summary for 4KCO

• Entry DOI: 10.2210/pdb4kco/pdb
• Related: 4KCH 4KCI 4KCJ 4KCK 4KCL 4KCM 4KCN 4KCP 4KCQ 4KCR 4KCS
• Descriptor: Nitric oxide synthase, brain, PROTOPORPHYRIN IX CONTAINING FE, 5,6,7,8-TETRAHYDROBIOPTERIN, ... (7 entities in total)
• Functional Keywords: nitric oxide synthase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Rattus norvegicus (rat)
• Cellular location: Cell membrane, sarcolemma ; Peripheral membrane protein : P29476
• Total number of polymer chains: 2
• Total formula weight: 100328.76

Authors

Li, H.,Poulos, T.L. (deposition date: 2013-04-24, release date: 2014-02-12, Last modification date: 2023-09-20)

Primary citation

Huang, H.,Li, H.,Yang, S.,Chreifi, G.,Martasek, P.,Roman, L.J.,Meyskens, F.L.,Poulos, T.L.,Silverman, R.B.
Potent and Selective Double-Headed Thiophene-2-carboximidamide Inhibitors of Neuronal Nitric Oxide Synthase for the Treatment of Melanoma.
J.Med.Chem., 57:686-700, 2014

PubMed 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.

PubMed: 24447275
DOI: 10.1021/jm401252e

Experimental method

X-RAY DIFFRACTION (1.86 Å)