5FVU

Structure of human nNOS R354A G357D mutant heme domain in complex with 4-methyl-6-(2-(5-(4-methylpiperazin-1-yl)pyridin-3-yl)ethyl) pyridin-2-amine

5FVU の概要

• エントリーDOI: 10.2210/pdb5fvu/pdb
• 関連するPDBエントリー: 5FVO 5FVP 5FVQ 5FVR 5FVS 5FVT 5FVV 5FVW 5FVX 5FVY 5FVZ 5FW0
• 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: oxidoreductase, nitric oxide synthase
• 由来する生物種: HOMO SAPIENS (HUMAN)
• 細胞内の位置: Cell membrane, sarcolemma; Peripheral membrane protein: P29475
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 100034.79

構造登録者

Li, H.,Poulos, T.L. (登録日: 2016-02-10, 公開日: 2016-04-20, 最終更新日: 2024-05-08)

主引用文献

Wang, H.,Qin, Y.,Li, H.,Roman, L.J.,Martasek, P.,Poulos, T.L.,Silverman, R.B.
Potent and Selective Human Neuronal Nitric Oxide Synthase Inhibition by Optimization of the 2-Aminopyridine-Based Scaffold with a Pyridine Linker.
J.Med.Chem., 59:4913-, 2016

PubMed Abstract: Neuronal nitric oxide synthase (nNOS) is an important therapeutic target for the treatment of various neurodegenerative disorders. A major challenge in the design of nNOS inhibitors focuses on potency in humans and selectivity over other NOS isoforms. Here we report potent and selective human nNOS inhibitors based on the 2-aminopyridine scaffold with a central pyridine linker. Compound 14j, the most promising inhibitor in this study, exhibits excellent potency for rat nNOS (Ki = 16 nM) with 828-fold n/e and 118-fold n/i selectivity with a Ki value of 13 nM against human nNOS with 1761-fold human n/e selectivity. Compound 14j also displayed good metabolic stability in human liver microsomes, low plasma protein binding, and minimal binding to cytochromes P450 (CYPs), although it had little to no Caco-2 permeability.

PubMed: 27050842
DOI: 10.1021/ACS.JMEDCHEM.6B00273

実験手法

X-RAY DIFFRACTION (2.224 Å)