4UPP

Structure of rat neuronal nitric oxide synthase heme domain in complex with N'-[4-[[(2S,4R)-4-[3-[(C-thiophen-2-ylcarbonimidoyl)amino]phenoxy]pyrrolidin-2-yl]methoxy]phenyl]thiophene-2-carboximidamide

4UPP の概要

• エントリーDOI: 10.2210/pdb4upp/pdb
• 関連するPDBエントリー: 4UPM 4UPN 4UPO 4UPQ 4UPR 4UPS 4UPT
• 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, inhibitor complex
• 由来する生物種: RATTUS NORVEGICUS (NORWAY RAT)
• 細胞内の位置: Cell membrane, sarcolemma; Peripheral membrane protein (By similarity): P29476
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 100559.35

構造登録者

Li, H.,Poulos, T.L. (登録日: 2014-06-17, 公開日: 2014-08-20, 最終更新日: 2024-05-08)

主引用文献

Jing, Q.,Li, H.,Roman, L.J.,Martasek, P.,Poulos, T.L.,Silverman, R.B.
Combination of Chiral Linkers with Thiophenecarboximidamide Heads to Improve the Selectivity of Inhibitors of Neuronal Nitric Oxide Synthase.
Bioorg.Med.Chem.Lett., 24:4504-, 2014

PubMed Abstract: To develop potent and selective nNOS inhibitors, a new series of double-headed molecules with chiral linkers that derive from natural amino acid derivatives have been designed and synthesized. The new structures integrate a thiophenecarboximidamide head with two types of chiral linkers, presenting easy synthesis and good inhibitory properties. Inhibitor (S)-9b exhibits a potency of 14.7 nM against nNOS and is 1134 and 322-fold more selective for nNOS over eNOS and iNOS, respectively. Crystal structures show that the additional binding between the aminomethyl moiety of 9b and propionate A on the heme and tetrahydrobiopterin (H4B) in nNOS, but not eNOS, contributes to its high selectivity. This work demonstrates the advantage of integrating known structures into structure optimization, and it should be possible to more readily develop compounds that incorporate bioavailability with these advanced features. Moreover, this integrative strategy is a general approach in new drug discovery.

PubMed: 25149509
DOI: 10.1016/J.BMCL.2014.07.079

実験手法

X-RAY DIFFRACTION (1.91 Å)