新型酪氨酸激酶小分子抑制的三维药效团研究

通过CATALYST软件包得到了两类HER2抑制的三维药效团模型。尽管亚苄基丙二腈化合物和3-取代吲哚啉-2-酮系列化合物具有完全不同的骨架结构，但得到的药效团却具有共同的特性，这表明当这两类抑制剂和受体发生相互作用时，采用了相似的结合模式。共同的药效团模型包括一个氢键受体，一个氢键给体，一个脂肪类疏水团以及一个芳香类疏水团。根据药效团模型，我们还进行了三维构效关系的研究，结果表明得到的药效团模型具有很好的预测能力(线性回归系数R≈0.96)。药效团模型对于研究酪氨酸激酶小分子抑制剂的结构与活性关系，以及评估和预测此类未知化合物活性具人重要的意义。

Pharmacophore model analysis of novel tyrphostins

A three-dimensional pharmacophore model of two types of HER2 inhibitors was obtained by using the CATALYST software. Although these inhibitors including 19 compounds of benzylidene malononitrile family and 13 compounds of 3-substituted indolin-2-ones family, possess quite different structures,a common pharmacophore model with very good stratistical results was determined. The common pharmacophore model included a hydrogen-bonding receptor, a hydrogen- bonding donor, an aliphatic hydrophobic core and and aromatic hydrophobic core. The results uncovered that these two types of molecules would take the similar pattern when they interact with the receptor. Based on the pharmacophore model a novel 3D-QSAR analysis was conducted, which showed very good predicitive ability (which linear correlation coefficient r≈0.96). This pharmacophore model is very useful for clarifying the structure-activity relationships of HER2 inhibitors and evaluateing new potential leading compounds.