9MZ4

Structure of human endothelial nitric oxide synthase heme domain bound 7-(3-(aminomethyl)-4-(cyclopropylmethoxy)phenyl)-6-fluoro-4-methylquinolin-2-amine

これはPDB形式変換不可エントリーです。

9MZ4 の概要

• エントリーDOI: 10.2210/pdb9mz4/pdb
• 分子名称: Nitric oxide synthase 3, CALCIUM ION, PROTOPORPHYRIN IX CONTAINING FE, ... (11 entities in total)
• 機能のキーワード: nitric oxide synthase inhibitor binding, oxidoreductase-inhibitor complex, 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: 205704.24

構造登録者

Li, H.,Poulos, T.L. (登録日: 2025-01-22, 公開日: 2025-12-03, 最終更新日: 2026-04-01)

主引用文献

Ansari, A.,Kang, K.M.,Li, H.,Hardy, C.D.,Rathnayake, A.D.,Awasthi, A.,Poulos, T.L.,Silverman, R.B.
Enhancement of Potency and Selectivity of 2-Aminoquinoline-Based Human Neuronal Nitric Oxide Synthase Inhibitors.
J.Med.Chem., 69:3779-3795, 2026

PubMed Abstract: Neuronal nitric oxide synthase (nNOS) is a key enzyme in neurodegenerative diseases and melanoma, making it an important therapeutic target. We previously reported 2-aminoquinoline-based nNOS inhibitors with promising activity but limited by suboptimal potency, isoform selectivity, and off-target effects. To address these issues, we designed and synthesized a new series of 7-aryl-6-fluoro-4-methyl-2-aminoquinoline derivatives. Compound showed excellent potency against human nNOS ( 16 nM), with ∼1800-fold selectivity over human endothelial NOS (eNOS) and ∼2900-fold over human inducible NOS (iNOS). PAMPA-BBB experiments indicated high effective permeability ( = 13.04 × 10 cm/s), suggesting strong CNS drug potential. pharmacokinetic studies in mice further demonstrated sustained systemic exposure, low clearance, and robust brain penetration. In contrast, compound , the -Me analogue of 16, was inactive. Molecular dynamics simulations indicated that -methylation disrupted the favorable solvation of the tail amino group, likely contributing to its loss of activity and nNOS affinity.

PubMed: 41635994
DOI: 10.1021/acs.jmedchem.5c01679

実験手法

X-RAY DIFFRACTION (1.94 Å)