KNI-10769 | 1215292-62-8

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 肽模拟物
• 英文名称: KNI-10769
• CAS: 1215292-62-8
• 化学式: C₃₃H₃₇N₃O₆S
• 分子量: 603.739
• InChiKey: YRCXUGKNFBNKLY-DOWNBTJOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.61
• 重原子数：
  43.0
• 可旋转键数：
  10.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  128.2
• 氢给体数：
  4.0
• 氢受体数：
  7.0

反应信息

• 作为产物：
  描述：

  (R)-3-((2S,3S)-3-amino-2-hydroxy-4-phenylbutanoyl)-N-((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-5,5-dimethylthiazolidine-4-carboxamide 、 苯氧乙酸 在 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 作用下， 生成 KNI-10769
  参考文献：
  名称：

  How Much Binding Affinity Can be Gained by Filling a Cavity?

  摘要：

  Binding affinity optimization is critical during drug development. Here, we evaluate the thermodynamic consequences of filling a binding cavity with functionalities of increasing van der Waals radii (–H, –F, –Cl, and CH3) that improve the geometric fit without participating in hydrogen bonding or other specific interactions. We observe a binding affinity increase of two orders of magnitude. There appears to be three phases in the process. The first phase is associated with the formation of stable van der Waals interactions. This phase is characterized by a gain in binding enthalpy and a loss in binding entropy, attributed to a loss of conformational degrees of freedom. For the specific case presented in this article, the enthalpy gain amounts to −1.5 kcal/mol while the entropic losses amount to +0.9 kcal/mol resulting in a net 3.5‐fold affinity gain. The second phase is characterized by simultaneous enthalpic and entropic gains. This phase improves the binding affinity 25‐fold. The third phase represents the collapse of the trend and is triggered by the introduction of chemical functionalities larger than the binding cavity itself [CH(CH3)2]. It is characterized by large enthalpy and affinity losses. The thermodynamic signatures associated with each phase provide guidelines for lead optimization.

  DOI：

  10.1111/j.1747-0285.2009.00921.x