(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 | 819083-90-4

• 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: (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
• CAS: 819083-90-4
• 化学式: C₂₅H₃₁N₃O₄S
• 分子量: 469.605
• InChiKey: BCDDOPIMXFMCBS-LILSUDLASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.37
• 重原子数：
  33.0
• 可旋转键数：
  6.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  115.89
• 氢给体数：
  4.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  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 在 盐酸 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 1-羟基苯并三唑 、 苯甲醚 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 1,4-二氧六环 、 N,N-二甲基甲酰胺 为溶剂， 生成 (R)-N-((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-3-((2S,3S)-2-hydroxy-3-((R)-3-(methylthio)-2-(4-oxo-4H-chromene-2-carboxamido)propanamido)-4-phenylbutanoyl)-5,5-dimethylthiazolidine-4-carboxamide
  参考文献：
  名称：

  Additional interaction of allophenylnorstatine-containing tripeptidomimetics with malarial aspartic protease plasmepsin II

  摘要：

  Based on a highly potent allophenylnorstatine-containing inhibitor, KNI-10006, against the plasmepsins of Plasmodium falciparum, we synthesized a series of tripeptide-type compounds with various N-terminal moieties and evaluated their inhibitory activities against plasmepsin II. Certain phenylacetyl derivatives exhibited extremely high affinity with Ki values of less than 0.1 nM suggesting successful hydrophobic interactions. (C) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2007.03.052
• 作为产物：
  描述：

  (R)-3-tert-butoxycarbonyl-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid 在 盐酸 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 1-羟基苯并三唑 、 苯甲醚 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 1,4-二氧六环 、 N,N-二甲基甲酰胺 为溶剂， 生成 (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
  参考文献：
  名称：

  Additional interaction of allophenylnorstatine-containing tripeptidomimetics with malarial aspartic protease plasmepsin II

  摘要：

  Based on a highly potent allophenylnorstatine-containing inhibitor, KNI-10006, against the plasmepsins of Plasmodium falciparum, we synthesized a series of tripeptide-type compounds with various N-terminal moieties and evaluated their inhibitory activities against plasmepsin II. Certain phenylacetyl derivatives exhibited extremely high affinity with Ki values of less than 0.1 nM suggesting successful hydrophobic interactions. (C) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2007.03.052

文献信息

• How Much Binding Affinity Can be Gained by Filling a Cavity?
  作者：Yuko Kawasaki、Eduardo E. Chufan、Virginie Lafont、Koushi Hidaka、Yoshiaki Kiso、L. Mario Amzel、Ernesto Freire

  DOI：10.1111/j.1747-0285.2009.00921.x

  日期：2010.2

  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.