EGFR酪氨酸激酶抑制剂的药效团模型构建

以80个作用方式相同, 分子结构特征不同的表皮生长因子受体酪氨酸激酶(EGFR TK)竞争性抑制剂为训练集, 利用计算机药物辅助软件Catalyst, 构建不同的药效团模型, 并结合酪氨酸激酶的作用位点等因素, 筛选出一个含有两个芳环中心, 一个疏水中心和一个阳离子基团的具有较好预测能力(RMS=0.438, Correl=0.908, Weight=1.52, Config=17.36)的药效团模型, 为设计和合成新型结构的EGFR TK抑制剂提供参考.

Construction of Pharmacophore Model of EGFR TK Inhibitor

Epidermal growth factor receptor (EGFR) protein tyrosine kinases (TK) are attractive targets for anti-tumor drug design. So, a good pharmacophore model of EGFR TK inhibitors will be propitious to design new EGFR TK inhibitors. 80 compounds reported EGFR TK inhibitors which work at the ATP-binding domain were chosen to construct several pharmacophore models with the help of Catalyst software. Based on the action mechanism and the 3D structure of the EGFR tyrosine kinases, a fitting pharmacophore model (RMS=0.438, Correl=0.908, Weight=1.52, Config=17.36) including two aromatic ring centers (RA), an aliphatic hydrophobic core (HP) and a positive ionizable center (PI) was confirmed. This model revealed that the RA and HP group may act on ATP binding pocket, and the PI may act on the surface of ATP binding pocket. Therefore, this study could provide new hints for denovo design of new EGFR inhibitors with observable structure and predictable activity (screened in silico).