9C1Y

Structure of human neuronal nitric oxide synthase R354A/G357D mutant heme domain in complex with 7-((3-(((4-(6-aminopyridin-2-yl)butyl)amino)methyl)phenoxy)methyl)quinolin-2-amine

9C1Y の概要

• エントリーDOI: 10.2210/pdb9c1y/pdb
• 分子名称: Nitric oxide synthase, brain, PROTOPORPHYRIN IX CONTAINING FE, 7-{[3-({[4-(6-aminopyridin-2-yl)butyl]amino}methyl)phenoxy]methyl}quinolin-2-amine, ... (6 entities in total)
• 機能のキーワード: nitric oxide synthase inhibitor, heme enzyme, oxidoreductase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 200846.62

構造登録者

Li, H.,Poulos, T.L. (登録日: 2024-05-29, 公開日: 2025-06-11, 最終更新日: 2025-08-06)

主引用文献

Weerawarna, P.M.,Li, H.,Rathnayake, A.D.,Hardy, C.D.,Poulos, T.L.,Silverman, R.B.
A Tetrahydrobiopterin-Displacing Potent Neuronal Nitric Oxide Synthase Inhibitor with an Unprecedented Binding Mode.
Acs Med.Chem.Lett., 16:651-659, 2025

PubMed Abstract: Nitric oxide synthase (NOS) is a pivotal enzyme that regulates various physiological processes, and the dysregulation of neuronal NOS (nNOS) is implicated in neurodegenerative diseases. In our efforts to leverage existing X-ray crystallography data to develop novel aminoquinoline-pyridine hybrid inhibitors and evaluate their inhibitory activities and interactions with NOS isoforms, we identified compounds and as potent human nNOS inhibitors ( = 38 and 22 nM, respectively). Notably, compound displayed an unprecedented binding mode, displacing the essential cofactor tetrahydrobiopterin (HB). Furthermore, compound exhibited excellent selectivity, with a 900-fold preference for human nNOS over human eNOS, making it one of the most potent and selective aminoquinoline-based nNOS inhibitors reported to date. Herein we present our inhibitor design rationale, the synthesis, and the biochemical/physical evaluation of binding along with X-ray crystallographic studies with three NOS isoforms, providing detailed insights into the observed potency and selectivity of these inhibitors.

PubMed: 40236557
DOI: 10.1021/acsmedchemlett.5c00062

実験手法

X-RAY DIFFRACTION (2.3 Å)