9MWI

Structure of rat neuronal nitric oxide synthase R349A mutant heme domain bound with N-(3-(2-((3-(thiazole-5-carboximidamido)benzyl)amino)ethyl)phenyl)thiazole-5-carboximidamide

これはPDB形式変換不可エントリーです。

9MWI の概要

• エントリーDOI: 10.2210/pdb9mwi/pdb
• 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
• 由来する生物種: Rattus norvegicus (Norway rat)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 50170.20

構造登録者

Li, H.,Poulos, T.L. (登録日: 2025-01-17, 公開日: 2025-11-26, 最終更新日: 2026-04-01)

主引用文献

Awasthi, A.,Patel, A.,Li, H.,Kang, K.M.,Hardy, C.D.,Ansari, A.,Nowar, R.,Hasan, M.E.,Yang, S.,Poulos, T.L.,Silverman, R.B.
New Inhibitors of Neuronal Nitric Oxide Synthase for the Treatment of Melanoma.
J.Med.Chem., 69:2310-2329, 2026

PubMed Abstract: In 2024, an estimated 100,640 new cases of invasive melanoma were diagnosed in the U.S., with 9290 deaths. Our previous studies revealed that neuronal nitric oxide synthase (nNOS) derived nitric oxide plays a critical role in melanoma progression, making nNOS inhibition a promising strategy. High structural similarity among NOS isoforms requires careful design of nNOS inhibitors to avoid off-target effects. Our previous lead, HH044, demonstrated potent antimelanoma activity but exhibited only moderate nNOS selectivity. Here, we utilized a structure-based approach to design nNOS inhibitors that promote interactions with human nNOS-specific residue His342. Compound exhibited inhibition of both human ( = 1.7 nM) and rat nNOS ( = 2.3 nM), with 5654-fold selectivity over human eNOS and 250-fold selectivity over iNOS. X-ray crystallography and molecular modeling revealed a novel SAR, forming the basis for nNOS inhibition and providing a foundation for further innovative design of nNOS inhibitors for melanoma treatment.

PubMed: 41615895
DOI: 10.1021/acs.jmedchem.5c02154

実験手法

X-RAY DIFFRACTION (2.054 Å)