2ORQ

Murine Inducible Nitric Oxide Synthase Oxygenase Domain (DELTA 114) 4-(imidazol-1-yl)phenol and piperonylamine Complex

2ORQ の概要

• エントリーDOI: 10.2210/pdb2orq/pdb
• 関連するPDBエントリー: 1DD7 1NOC 1NOD 1NOS 1NSI 2NOS 2ORO 2ORP 2ORR 2ORS 2ORT
• 分子名称: Nitric oxide synthase, inducible, PROTOPORPHYRIN IX CONTAINING FE, 4-(1H-IMIDAZOL-1-YL)PHENOL, ... (5 entities in total)
• 機能のキーワード: nitric oxide, l-arginine monooxygenase, heme, dimerization, inhibitor, nos, oxidoreductase
• 由来する生物種: Mus musculus (house mouse)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 46198.20

構造登録者

Adler, M.,Whitlow, M. (登録日: 2007-02-04, 公開日: 2007-04-17, 最終更新日: 2024-02-21)

主引用文献

Davey, D.D.,Adler, M.,Arnaia, D.,Eagen, K.,Erickson, S.,Guilford, W.,Kenrick, M.,Morrissey, M.M.,Ohimeyer, M.,Pan, G.,Paradkar, V.M.,Parkinson, J.,Polokoff, M.,Salonz, K.,Santos, C.,Subramanyam, B.,Vergona, R.,Wei, R.G.,Whitlow, M.,Ye, B.,Zhao, Z.S.,Devlin, J.J.,Phillips, G.
Design, Synthesis, and Activity of 2-Imidazol-1-ylpyrimidine Derived Inducible Nitric Oxide Synthase Dimerization Inhibitors
J.Med.Chem., 50:1146-1157, 2007

PubMed Abstract: By the screening of a combinatorial library for inhibitors of nitric oxide (NO) formation by the inducible isoform of nitric oxide synthase (iNOS) using a whole-cell assay, 2-(imidazol-1-yl)pyrimidines were identified. Compounds were found to inhibit the dimerization of iNOS monomers, thus preventing the formation of the dimeric, active form of the enzyme. Optimization led to the selection of the potent, selective, and orally available iNOS dimerization inhibitor, 21b, which significantly ameliorated adjuvant-induced arthritis in a rat model. Analysis of the crystal structure of the 21b--iNOS monomer complex provided a rationalization for both the SAR and the mechanism by which 21b blocks the formation of the protein--protein interaction present in the dimeric form of iNOS.

PubMed: 17315988
DOI: 10.1021/jm061319i

実験手法

X-RAY DIFFRACTION (2.1 Å)