5UO1

Structure of human neuronal nitric oxide synthase heme domain in complex with 3-[(2-aminoquinolin-7-yl)methoxy]-5-((methylamino)methyl)benzonitrile

5UO1 の概要

• エントリーDOI: 10.2210/pdb5uo1/pdb
• 関連するPDBエントリー: 5UNR 5UNS 5UNT 5UNU 5UNV 5UNW 5UNX 5UNY 5UNZ 5UO0 5UO2 5UO3 5UO4 5UO5 5UO6 5UO7 5UO8 5UO9 5UOA 5UOB 5UOC 5UOD
• 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, inhibitor, complex, heme, enzyme, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 100078.71

構造登録者

Li, H.,Poulos, T.L. (登録日: 2017-01-31, 公開日: 2017-05-03, 最終更新日: 2023-10-04)

主引用文献

Cinelli, M.A.,Li, H.,Chreifi, G.,Poulos, T.L.,Silverman, R.B.
Nitrile in the Hole: Discovery of a Small Auxiliary Pocket in Neuronal Nitric Oxide Synthase Leading to the Development of Potent and Selective 2-Aminoquinoline Inhibitors.
J. Med. Chem., 60:3958-3978, 2017

PubMed Abstract: Neuronal nitric oxide synthase (nNOS) inhibition is a promising strategy to treat neurodegenerative disorders, but the development of nNOS inhibitors is often hindered by poor pharmacokinetics. We previously developed a class of membrane-permeable 2-aminoquinoline inhibitors and later rearranged the scaffold to decrease off-target binding. However, the resulting compounds had decreased permeability, low human nNOS activity, and low selectivity versus human eNOS. In this study, 5-substituted phenyl ether-linked aminoquinolines and derivatives were synthesized and assayed against purified NOS isoforms. 5-Cyano compounds are especially potent and selective rat and human nNOS inhibitors. Activity and selectivity are mediated by the binding of the cyano group to a new auxiliary pocket in nNOS. Potency was enhanced by methylation of the quinoline and by introduction of simple chiral moieties, resulting in a combination of hydrophobic and auxiliary pocket effects that yielded high (∼500-fold) n/e selectivity. Importantly, the Caco-2 assay also revealed improved membrane permeability over previous compounds.

PubMed: 28422508
DOI: 10.1021/acs.jmedchem.7b00259

実験手法

X-RAY DIFFRACTION (1.9 Å)