4UCH

Structure of human nNOS R354A G357D mutant heme domain in complex with 3-(((2-((2-(1H-IMIDAZOL-1-YL)PYRIMIDIN-4-YL)ETHYL)AMINO)METHYL) BENZONITRILE

4UCH の概要

• エントリーDOI: 10.2210/pdb4uch/pdb
• 分子名称: NITRIC OXIDE SYNTHASE, BRAIN, PROTOPORPHYRIN IX CONTAINING FE, 5,6,7,8-TETRAHYDROBIOPTERIN, ... (6 entities in total)
• 機能のキーワード: oxidoreductase
• 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: 100072.67

構造登録者

Li, H.,Poulos, T.L. (登録日: 2014-12-03, 公開日: 2014-12-24, 最終更新日: 2023-12-20)

主引用文献

Mukherjee, P.,Li, H.,Sevrioukova, I.,Chreifi, G.,Martasek, P.,Roman, L.J.,Poulos, T.L.,Silverman, R.B.
Novel 2,4-Disubstituted Pyrimidines as Potent, Selective, and Cell-Permeable Inhibitors of Neuronal Nitric Oxide Synthase.
J.Med.Chem., 58:1067-, 2015

PubMed Abstract: Selective inhibition of neuronal nitric oxide synthase (nNOS) is an important therapeutic approach to target neurodegenerative disorders. However, the majority of the nNOS inhibitors developed are arginine mimetics and, therefore, suffer from poor bioavailability. We designed a novel strategy to combine a more pharmacokinetically favorable 2-imidazolylpyrimidine head with promising structural components from previous inhibitors. In conjunction with extensive structure-activity studies, several highly potent and selective inhibitors of nNOS were discovered. X-ray crystallographic analysis reveals that these type II inhibitors utilize the same hydrophobic pocket to gain strong inhibitory potency (13), as well as high isoform selectivity. Interestingly, select compounds from this series (9) showed good permeability and low efflux in a Caco-2 assay, suggesting potential oral bioavailability, and exhibited minimal off-target binding to 50 central nervous system receptors. Furthermore, even with heme-coordinating groups in the molecule, modifying other pharmacophoric fragments minimized undesirable inhibition of cytochrome P450s from human liver microsomes.

PubMed: 25489882
DOI: 10.1021/JM501719E

実験手法

X-RAY DIFFRACTION (2.2 Å)