3-[[2-[[4-[N'-[4-[[(3S)-4-[3-[2-[2-[3-[5-[(3aS,4S,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]propoxy]ethoxy]ethoxy]propylamino]-4-oxo-3-[[4-[3-(trifluoromethyl)diazirin-3-yl]benzoyl]amino]butanoyl]amino]butyl]carbamimidoyl]anilino]methyl]-1-methylbenzimidazole-5-carbonyl]-pyridin-2-ylamino]propanoic acid | 1373169-91-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 生物素及其衍生物
• 英文名称: 3-[[2-[[4-[N'-[4-[[(3S)-4-[3-[2-[2-[3-[5-[(3aS,4S,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]propoxy]ethoxy]ethoxy]propylamino]-4-oxo-3-[[4-[3-(trifluoromethyl)diazirin-3-yl]benzoyl]amino]butanoyl]amino]butyl]carbamimidoyl]anilino]methyl]-1-methylbenzimidazole-5-carbonyl]-pyridin-2-ylamino]propanoic acid
• CAS: 1373169-91-5
• 化学式: C₆₂H₇₈F₃N₁₅O₁₁S
• 分子量: 1298.46
• InChiKey: FWPJLUJFQUSPKW-QZMVMWQSSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  92
• 可旋转键数：
  39
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  374
• 氢给体数：
  9
• 氢受体数：
  21

反应信息

• 作为产物：
  描述：

  C₆₄H₈₂F₃N₁₅O₁₁S 在 水 、 lithium hydroxide 作用下， 以 四氢呋喃 为溶剂， 反应 17.0h， 以48%的产率得到3-[[2-[[4-[N'-[4-[[(3S)-4-[3-[2-[2-[3-[5-[(3aS,4S,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]propoxy]ethoxy]ethoxy]propylamino]-4-oxo-3-[[4-[3-(trifluoromethyl)diazirin-3-yl]benzoyl]amino]butanoyl]amino]butyl]carbamimidoyl]anilino]methyl]-1-methylbenzimidazole-5-carbonyl]-pyridin-2-ylamino]propanoic acid
  参考文献：
  名称：

  Dabigatran and Dabigatran Ethyl Ester: Potent Inhibitors of Ribosyldihydronicotinamide Dehydrogenase (NQO2)

  摘要：

  Recent studies have revealed that compounds believed to be highly selective frequently address multiple target proteins. We investigated the protein interaction profile of the widely prescribed thrombin inhibitor dabigatran (1), resulting in the identification and subsequent characterization of an additional target enzyme. Our findings are based on an unbiased functional proteomics approach called capture compound mass spectrometry (CCMS) and were confirmed by independent biological assays. 1 was shown to specifically bind ribosyldihydronicotinamide dehydrogenase (NQO2), a detoxification oxidoreductase. Molecular dockings predicted and biological experiments confirmed that dabigatran ethyl ester (2) inhibits NQO2 even more effectively than the parent 1 itself. Our data show that 1 and 2 are inhibitors of NQO2, thereby revealing a possible new aspect in the mode of action of 1. We present a workflow employing chemical proteomics, molecular modeling, and functional assays by which a compound's protein-interaction profile can be determined and used to tune the binding affinity.

  DOI：

  10.1021/jm3001339

文献信息

• Dabigatran and Dabigatran Ethyl Ester: Potent Inhibitors of Ribosyldihydronicotinamide Dehydrogenase (NQO2)
  作者：Simon Michaelis、Anett Marais、Anna K. Schrey、Olivia Y. Graebner、Cornelia Schaudt、Michael Sefkow、Friedrich Kroll、Mathias Dreger、Mirko Glinski、Hubert Koester、Rainer Metternich、Jenny J. Fischer

  DOI：10.1021/jm3001339

  日期：2012.4.26

  Recent studies have revealed that compounds believed to be highly selective frequently address multiple target proteins. We investigated the protein interaction profile of the widely prescribed thrombin inhibitor dabigatran (1), resulting in the identification and subsequent characterization of an additional target enzyme. Our findings are based on an unbiased functional proteomics approach called capture compound mass spectrometry (CCMS) and were confirmed by independent biological assays. 1 was shown to specifically bind ribosyldihydronicotinamide dehydrogenase (NQO2), a detoxification oxidoreductase. Molecular dockings predicted and biological experiments confirmed that dabigatran ethyl ester (2) inhibits NQO2 even more effectively than the parent 1 itself. Our data show that 1 and 2 are inhibitors of NQO2, thereby revealing a possible new aspect in the mode of action of 1. We present a workflow employing chemical proteomics, molecular modeling, and functional assays by which a compound's protein-interaction profile can be determined and used to tune the binding affinity.