methyl (E)-2-[2-[[(2-benzothiazolyl)thio]-methyl]phenyl]-3-methoxy-2-propenoate | 120973-89-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: methyl (E)-2-[2-[[(2-benzothiazolyl)thio]-methyl]phenyl]-3-methoxy-2-propenoate
• 英文别名: e-Methyl 2-(2-((benzo-thiazol-2-ylthio)methyl)phenyl)-3-methoxyacrylate；methyl (E)-2-[2-(1,3-benzothiazol-2-ylsulfanylmethyl)phenyl]-3-methoxyprop-2-enoate
• CAS: 120973-89-9
• 化学式: C₁₉H₁₇NO₃S₂
• 分子量: 371.481
• InChiKey: NCEIEWKQCZHKNX-RVDMUPIBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  25
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.16
• 拓扑面积：
  102
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  2-巯基苯并噻唑 、 (E)-3-甲氧基-2-(2-溴甲基苯基)丙烯酸甲酯 在 sodium hydroxide 作用下， 以 水 、 N,N-二甲基甲酰胺 为溶剂， 以80%的产率得到methyl (E)-2-[2-[[(2-benzothiazolyl)thio]-methyl]phenyl]-3-methoxy-2-propenoate
  参考文献：
  名称：

  Computational Discovery of Picomolar Q_o Site Inhibitors of Cytochrome bc₁ Complex

  摘要：

  A critical challenge to the fragment-based drug discovery (FBDD) is its low-throughput nature due to the necessity of biophysical method-based fragment screening. Herein, a method of pharmacophore-linked fragment virtual screening (PFVS) was successfully developed. Its application yielded the first picomolar-range Q(o) site inhibitors of the cytochrome bc(1) complex, an important membrane protein for drug and fungicide discovery. Compared with the original hit compound 4 (K-i = 881.80 nM, porcine bc(1)), the most potent compound 4f displayed 20 507-fold improved binding affinity (K-i = 43.00 pM). Compound 4f was proved to be a noncompetitive inhibitor with respect to the substrate cytochrome c, but a competitive inhibitor with respect to the substrate ubiquinol. Additionally, we determined the crystal structure of compound 4e (K-i = 83.00 pM) bound to the chicken bc(1) at 2.70 angstrom resolution, providing a molecular basis for understanding its ultrapotency. To our knowledge, this study is the first application of the FBDD method in the discovery of picomolar inhibitors of a membrane protein. This work demonstrates that the novel PFVS approach is a high-throughput drug discovery method, independent of biophysical screening techniques.

  DOI：

  10.1021/ja3001908

文献信息

• Computational Discovery of Picomolar <i>Q</i>_o Site Inhibitors of Cytochrome <i>bc</i>₁ Complex
  作者：Ge-Fei Hao、Fu Wang、Hui Li、Xiao-Lei Zhu、Wen-Chao Yang、Li-Shar Huang、Jia-Wei Wu、Edward A. Berry、Guang-Fu Yang

  DOI：10.1021/ja3001908

  日期：2012.7.11

  A critical challenge to the fragment-based drug discovery (FBDD) is its low-throughput nature due to the necessity of biophysical method-based fragment screening. Herein, a method of pharmacophore-linked fragment virtual screening (PFVS) was successfully developed. Its application yielded the first picomolar-range Q(o) site inhibitors of the cytochrome bc(1) complex, an important membrane protein for drug and fungicide discovery. Compared with the original hit compound 4 (K-i = 881.80 nM, porcine bc(1)), the most potent compound 4f displayed 20 507-fold improved binding affinity (K-i = 43.00 pM). Compound 4f was proved to be a noncompetitive inhibitor with respect to the substrate cytochrome c, but a competitive inhibitor with respect to the substrate ubiquinol. Additionally, we determined the crystal structure of compound 4e (K-i = 83.00 pM) bound to the chicken bc(1) at 2.70 angstrom resolution, providing a molecular basis for understanding its ultrapotency. To our knowledge, this study is the first application of the FBDD method in the discovery of picomolar inhibitors of a membrane protein. This work demonstrates that the novel PFVS approach is a high-throughput drug discovery method, independent of biophysical screening techniques.