1-ethyl-3-(5-(thiophene-2-carbonyl)-1H-benzo[d]imidazol-2-yl)urea | 1438897-47-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并咪唑类
• 英文名称: 1-ethyl-3-(5-(thiophene-2-carbonyl)-1H-benzo[d]imidazol-2-yl)urea
• 英文别名: 1-ethyl-3-[6-(thiophene-2-carbonyl)-1H-benzimidazol-2-yl]urea
• CAS: 1438897-47-2
• 化学式: C₁₅H₁₄N₄O₂S
• 分子量: 314.368
• InChiKey: YSQMWNBUNGYNRT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  22
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.13
• 拓扑面积：
  115
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  3,4-二硝基苯甲酸 在 aluminum (III) chloride 、 氯化亚砜 、 tin(II) chloride dihdyrate 、 溶剂黄146 作用下， 以 乙醇 、 二氯甲烷 、 水 为溶剂， 反应 27.0h， 生成 1-ethyl-3-(5-(thiophene-2-carbonyl)-1H-benzo[d]imidazol-2-yl)urea
  参考文献：
  名称：

  Discovery of Picomolar ABL Kinase Inhibitors Equipotent for Wild Type and T315I Mutant via Structure-Based de Novo Design

  摘要：

  Although the constitutively activated break-point cluster region-Abelson (ABL) tyrosine kinase is known to cause chronic myelogenous leukemia (CML), the prevalence of drug-resistant ABL mutants has made it difficult to develop effective anti-CML drugs. With the aim to identify new lead compounds for anti-CML drugs, we carried out a structure-based de novo design using the scoring function improved by implementing an accurate solvation free energy term. This approach led to the identification of ABL inhibitors equipotent for the wild type and the most drug-resistant T315I mutant of ABL at the picomolar level. Decomposition analysis of the binding free energy showed that a decrease in the desolvation cost for binding in the ATP-binding site could be as important as the strengthening of enzyme-inhibitor interaction to enhance the potency of an ABL inhibitor with structural modifications. A similar energetic feature was also observed in free energy perturbation (FEP) calculations. Consistent with the previous experimental and computational studies, the hydrogen bond interactions with the backbone groups of Met318 proved to be the most significant binding forces to stabilize the inhibitors in the ATP-binding sites of the wild type and T315I mutant. The results of molecular dynamics simulations indicated that the dynamic stabilities of the hydrogen bonds between the inhibitors and Met318 should also be considered in designing the potent common inhibitors of the wild-type and T315I mutant of ABL.

  DOI：

  10.1021/ja311756u

文献信息

• Discovery of Picomolar ABL Kinase Inhibitors Equipotent for Wild Type and T315I Mutant via Structure-Based de Novo Design
  作者：Hwangseo Park、Seunghee Hong、Jinhee Kim、Sungwoo Hong

  DOI：10.1021/ja311756u

  日期：2013.6.5

  Although the constitutively activated break-point cluster region-Abelson (ABL) tyrosine kinase is known to cause chronic myelogenous leukemia (CML), the prevalence of drug-resistant ABL mutants has made it difficult to develop effective anti-CML drugs. With the aim to identify new lead compounds for anti-CML drugs, we carried out a structure-based de novo design using the scoring function improved by implementing an accurate solvation free energy term. This approach led to the identification of ABL inhibitors equipotent for the wild type and the most drug-resistant T315I mutant of ABL at the picomolar level. Decomposition analysis of the binding free energy showed that a decrease in the desolvation cost for binding in the ATP-binding site could be as important as the strengthening of enzyme-inhibitor interaction to enhance the potency of an ABL inhibitor with structural modifications. A similar energetic feature was also observed in free energy perturbation (FEP) calculations. Consistent with the previous experimental and computational studies, the hydrogen bond interactions with the backbone groups of Met318 proved to be the most significant binding forces to stabilize the inhibitors in the ATP-binding sites of the wild type and T315I mutant. The results of molecular dynamics simulations indicated that the dynamic stabilities of the hydrogen bonds between the inhibitors and Met318 should also be considered in designing the potent common inhibitors of the wild-type and T315I mutant of ABL.