4UH6

Structure of human nNOS R354A G357D mutant heme domain in complex with 3-(2-(6-Amino-4-methylpyridin-2-yl)ethyl)-5-(methyl(2-(methylamino)ethyl)amino)benzonitrile

4UH6 の概要

• エントリーDOI: 10.2210/pdb4uh6/pdb
• 関連するPDBエントリー: 4UGZ 4UH0 4UH1 4UH2 4UH3 4UH4 4UH5 4UH7 4UH8 4UH9 4UHA
• 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
• 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: 100067.65

構造登録者

Li, H.,Poulos, T.L. (登録日: 2015-03-23, 公開日: 2015-07-15, 最終更新日: 2024-05-08)

主引用文献

Kang, S.,Li, H.,Tang, W.,Martasek, P.,Roman, L.J.,Poulos, T.L.,Silverman, R.B.
2-Aminopyridines with a Truncated Side Chain to Improve Human Neuronal Nitric Oxide Synthase Inhibitory Potency and Selectivity.
J.Med.Chem., 58:5548-, 2015

PubMed Abstract: We have analyzed a recently obtained crystal structure of human neuronal nitric oxide synthase (nNOS) and then designed and synthesized several 2-aminopyridine derivatives containing a truncated side chain to avoid the hydrophobic pocket that differentiates human and rat nNOS in an attempt to explore alternative binding poses along the substrate access channel of human nNOS. Introduction of an N-methylethane-1,2-diamine side chain and conformational constraints such as benzonitrile and pyridine as the middle aromatic linker were sufficient to increase human and rat nNOS binding affinity and inducible and endothelial NOS selectivity. We found that 14b is a potent inhibitor; the binding modes with human and rat nNOS are unexpected, inducing side chain rotamer changes in Gln478 (rat) at the top of the active site. Compound 19c exhibits Ki values of 24 and 55 nM for rat and human nNOS, respectively, with 153-fold iNOS and 1040-fold eNOS selectivity. 19c has 18% oral bioavailability.

PubMed: 26120733
DOI: 10.1021/ACS.JMEDCHEM.5B00573

実験手法

X-RAY DIFFRACTION (1.98 Å)