(S)-2-((2S,3R)-2-((S)-1-((S)-2-acetamido-3-(phosphonooxy)propanoyl)pyrrolidine-2-carboxamido)-3-hydroxybutanamido)-3-phenylpropanoic acid | 1310583-48-2

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (S)-2-((2S,3R)-2-((S)-1-((S)-2-acetamido-3-(phosphonooxy)propanoyl)pyrrolidine-2-carboxamido)-3-hydroxybutanamido)-3-phenylpropanoic acid
• 英文别名: (2S)-2-[[(2S,3R)-2-[[(2S)-1-[(2S)-2-acetamido-3-phosphonooxypropanoyl]pyrrolidine-2-carbonyl]amino]-3-hydroxybutanoyl]amino]-3-phenylpropanoic acid
• CAS: 1310583-48-2
• 化学式: C₂₃H₃₃N₄O₁₁P
• 分子量: 572.509
• InChiKey: OUZKGDVFUKUREZ-RUZYHRDJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -2.1
• 重原子数：
  39
• 可旋转键数：
  13
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  232
• 氢给体数：
  7
• 氢受体数：
  11

反应信息

• 作为产物：
  描述：

  Fmoc-L-脯氨酸 、 Fmoc-L-苯丙氨酸 、 乙酸酐 、 Fmoc-Thr-OH 、 Fmoc-O-磷酰-L-丝氨酸 在 1-羟基苯并三唑 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 N,N-二异丙基乙胺 作用下， 以 N-甲基吡咯烷酮 为溶剂， 反应 1.08h， 生成 (S)-2-((2S,3R)-2-((S)-1-((S)-2-acetamido-3-(phosphonooxy)propanoyl)pyrrolidine-2-carboxamido)-3-hydroxybutanamido)-3-phenylpropanoic acid
  参考文献：
  名称：

  Exploiting the P-1 Pocket of BRCT Domains Toward a Structure Guided Inhibitor Design

  摘要：

  Breast cancer gene 1 carboxy terminus (BRCT) domains are found in a number of proteins that are important for DNA damage response (DDR). The BRCT domains bind phosphorylated proteins, and these protein-protein interactions are essential for DDR and DNA repair. High affinity domain specific inhibitors are needed to facilitate the dissection of the protein-protein interactions in the DDR signaling. The BRCT domains of BRCA1 bind phosphorylated protein through a pSXXF consensus recognition motif We identified a hydrophobic pocket at the P-1 position of the pSXXF binding site. Here we conducted a structure-guided synthesis of peptide analogues with hydrophobic functional groups at the P-1 position. Evaluation of these led to the identification of a peptide mimic 15 with a inhibitory constant (K(i)) of 40 nM for BRCT(BRCA1). Analysis of the TopBP1 and MDC1 BRCT domains suggests a similar approach is viable to design high affinity inhibitors.

  DOI：

  10.1021/ml200147a

文献信息

• Exploiting the P-1 Pocket of BRCT Domains Toward a Structure Guided Inhibitor Design
  作者：Ziyan Yuan、Eric A. Kumar、Stephen J. Campbell、Nicholas Y. Palermo、Smitha Kizhake、J. N. Mark Glover、Amarnath Natarajan

  DOI：10.1021/ml200147a

  日期：2011.10.13

  Breast cancer gene 1 carboxy terminus (BRCT) domains are found in a number of proteins that are important for DNA damage response (DDR). The BRCT domains bind phosphorylated proteins, and these protein-protein interactions are essential for DDR and DNA repair. High affinity domain specific inhibitors are needed to facilitate the dissection of the protein-protein interactions in the DDR signaling. The BRCT domains of BRCA1 bind phosphorylated protein through a pSXXF consensus recognition motif We identified a hydrophobic pocket at the P-1 position of the pSXXF binding site. Here we conducted a structure-guided synthesis of peptide analogues with hydrophobic functional groups at the P-1 position. Evaluation of these led to the identification of a peptide mimic 15 with a inhibitory constant (K(i)) of 40 nM for BRCT(BRCA1). Analysis of the TopBP1 and MDC1 BRCT domains suggests a similar approach is viable to design high affinity inhibitors.