5ADC

Structure of rat neuronal nitric oxide synthase heme domain in complex with 7-(((5-((Methylamino)methyl)pyridin-3-yl)oxy)methyl) quinolin-2-amine

5ADC の概要

• エントリーDOI: 10.2210/pdb5adc/pdb
• 関連するPDBエントリー: 5AD4 5AD5 5AD6 5AD7 5AD8 5AD9 5ADA 5ADB 5ADD 5ADE 5ADF 5ADG 5ADI 5ADJ 5ADK 5ADL 5ADM 5ADN
• 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, inhibitor complex
• 由来する生物種: RATTUS NORVEGICUS (NORWAY 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: 100108.69

構造登録者

Li, H.,Poulos, T.L. (登録日: 2015-08-20, 公開日: 2015-10-28, 最終更新日: 2024-05-08)

主引用文献

Cinelli, M.A.,Li, H.,Pensa, A.V.,Kang, S.,Roman, L.J.,Martasek, P.,Poulos, T.L.,Silverman, R.B.
Phenyl Ether- and Aniline-Containing 2-Aminoquinolines as Potent and Selective Inhibitors of Neuronal Nitric Oxide Synthase.
J.Med.Chem., 58:8694-, 2015

PubMed Abstract: Excess nitric oxide (NO) produced by neuronal nitric oxide synthase (nNOS) is implicated in neurodegenerative disorders. As a result, inhibition of nNOS and reduction of NO levels is desirable therapeutically, but many nNOS inhibitors are poorly bioavailable. Promising members of our previously reported 2-aminoquinoline class of nNOS inhibitors, although orally bioavailable and brain-penetrant, suffer from unfavorable off-target binding to other CNS receptors, and they resemble known promiscuous binders. Rearranged phenyl ether- and aniline-linked 2-aminoquinoline derivatives were therefore designed to (a) disrupt the promiscuous binding pharmacophore and diminish off-target interactions and (b) preserve potency, isoform selectivity, and cell permeability. A series of these compounds was synthesized and tested against purified nNOS, endothelial NOS (eNOS), and inducible NOS (iNOS) enzymes. One compound, 20, displayed high potency, selectivity, and good human nNOS inhibition, and retained some permeability in a Caco-2 assay. Most promisingly, CNS receptor counterscreening revealed that this rearranged scaffold significantly reduces off-target binding.

PubMed: 26469213
DOI: 10.1021/ACS.JMEDCHEM.5B01330

実験手法

X-RAY DIFFRACTION (2.1 Å)