物理化学学报 >> 2008, Vol. 24 >> Issue (02): 281-288.doi: 10.3866/PKU.WHXB20080217

研究论文 上一篇    下一篇

EGFR酪氨酸激酶抑制剂的药效团模型构建

陈曦; 刘心霞; 黄慧; 胡慧慧; 姜凤超   

  1. 华中科技大学同济医学院药学院, 武汉 430030
  • 收稿日期:2007-07-23 修回日期:2007-11-02 发布日期:2008-01-26
  • 通讯作者: 姜凤超 E-mail:fengchao@mails.tjmu.edu.cn

Construction of PharmacophoreModel of EGFRTK Inhibitor

CHEN Xi; LIU Xin-Xia; HUANG Hui; HU Hui-Hui; JIANG Feng-Chao   

  1. School of Pharmacy, Tongji Medical Colloge, Huazhong Science and Technology University, Wuhan 430030, P. R. China
  • Received:2007-07-23 Revised:2007-11-02 Published:2008-01-26
  • Contact: JIANG Feng-Chao E-mail:fengchao@mails.tjmu.edu.cn

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摘要： 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.

关键词: 抗肿瘤药物, 计算机辅助药物设计, EGFR抑制剂, 药效团模型

Abstract: 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).

Key words: Antitumor drug, Computer aided drug design, EGFR inhibitor, Pharmacophore model

MSC2000: 

  • O641