4KCL

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

4KCL の概要

• エントリーDOI: 10.2210/pdb4kcl/pdb
• 関連するPDBエントリー: 4KCH 4KCI 4KCJ 4KCK 4KCM 4KCN 4KCO 4KCP 4KCQ 4KCR 4KCS
• 分子名称: Nitric oxide synthase, brain, PROTOPORPHYRIN IX CONTAINING FE, 5,6,7,8-TETRAHYDROBIOPTERIN, ... (7 entities in total)
• 機能のキーワード: nitric oxide synthase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Rattus norvegicus (rat)
• 細胞内の位置: Cell membrane, sarcolemma ; Peripheral membrane protein : P29476
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 100443.28

構造登録者

Li, H.,Poulos, T.L. (登録日: 2013-04-24, 公開日: 2014-02-12, 最終更新日: 2023-09-20)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.93 Å)