3UFV

Structure of rat nitric oxide synthase heme domain in complex with 4-methyl-6-(((3R,4R)-4-((5-(4-methylpyridin-2-yl)pentyl)oxy)pyrrolidin-3-yl)methyl)pyridin-2-amine

3UFV の概要

• エントリーDOI: 10.2210/pdb3ufv/pdb
• 関連するPDBエントリー: 3UFO 3UFP 3UFQ 3UFR 3UFS 3UFT 3UFU 3UFW
• 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 binding, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Rattus norvegicus (brown rat,rat,rats)
• 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: 100261.05

構造登録者

Li, H.,Poulos, T.L. (登録日: 2011-11-01, 公開日: 2012-07-11, 最終更新日: 2023-09-13)

主引用文献

Huang, H.,Ji, H.,Li, H.,Jing, Q.,Labby, K.J.,Martasek, P.,Roman, L.J.,Poulos, T.L.,Silverman, R.B.
Selective monocationic inhibitors of neuronal nitric oxide synthase. Binding mode insights from molecular dynamics simulations.
J.Am.Chem.Soc., 134:11559-11572, 2012

PubMed Abstract: The reduction of pathophysiologic levels of nitric oxide through inhibition of neuronal nitric oxide synthase (nNOS) has the potential to be therapeutically beneficial in various neurodegenerative diseases. We have developed a series of pyrrolidine-based nNOS inhibitors that exhibit excellent potencies and isoform selectivities (J. Am. Chem. Soc. 2010, 132, 5437). However, there are still important challenges, such as how to decrease the multiple positive charges derived from basic amino groups, which contribute to poor bioavailability, without losing potency and/or selectivity. Here we present an interdisciplinary study combining molecular docking, crystallography, molecular dynamics simulations, synthesis, and enzymology to explore potential pharmacophoric features of nNOS inhibitors and to design potent and selective monocationic nNOS inhibitors. The simulation results indicate that different hydrogen bond patterns, electrostatic interactions, hydrophobic interactions, and a water molecule bridge are key factors for stabilizing ligands and controlling ligand orientation. We find that a heteroatom in the aromatic head or linker chain of the ligand provides additional stability and blocks the substrate binding pocket. Finally, the computational insights are experimentally validated with double-headed pyridine analogues. The compounds reported here are among the most potent and selective monocationic pyrrolidine-based nNOS inhibitors reported to date, and 10 shows improved membrane permeability.

PubMed: 22731813
DOI: 10.1021/ja302269r

実験手法

X-RAY DIFFRACTION (2.078 Å)