作用于ftase和raf-1激酶的新型抗肿瘤药物的设计.pdfVIP

170 药学学报 Acta Pharmaceutica Sinica 20 11, 46 (2) : 170 178 作用于FTase 和Raf-1 激酶的新型抗肿瘤药物的设计 娟, 朱一婧, 曾 露, 王 茜, 姜凤超* (华中科技大学同济医学院药学院, 湖北 武汉 430030) 摘要: Ras/Raf/MEK/ERK 信号通路, 在肿瘤细胞的增殖、分化、凋亡、转移、代谢等过程中起着重要的作用, 本文着眼于Ras/Raf/MEK/ERK 信号通路中的关键靶点, 以法尼基转移酶 (FTase) 为主靶点, 以Raf-1 激酶为次 靶点, 借助计算机辅助药物设计 (CADD), 构建法尼基转移酶抑制剂 (FTIs) 和Raf-1 激酶抑制剂的药效团模型, 设计出同时与这两个靶点相匹配的多靶点配体药物。所设计的多靶点配体药物以氨 基苯甲酸为母核结构, 具 有较好的预测活性。 关键词: 多靶点配体药物; 信号转导; 药效团模型; 法尼基转移酶; Raf-1 激酶 中图分类号: R916 文献标识码:A 文章编号: 05 13-4870 (20 11) 02-0170-09 The design of muti-target antitumor drugs affecting on FTase and Raf-1 kinase * ZHAO Juan, ZHU Yi-ji ng, ZENG Lu, WANG Qian, JIANG Feng-chao (School of Pharmacy, Tongj i M edical College, Huazhong University of Science and Technology, Wuhan 430030, China) Abstract: Ras/Raf/MEK/ERK singal transduction plays an important role in cell proliferation, differentiation, apoptosis, metastasis and metabolism. This investigation focused on this singal pathway and chose farnesyl transferase (FTase) as the main target and Raf-1 kinase as the second target. A lot of compounds were selected to construct the pharmacophore models of farnesyl transferase inhibitors (FTIs) and Raf-1 kinase inhibitors by using computer-aided drug design (CADD). The pharmacophore of FTIs is constituted by a hydrogen bonding acceptor, an aromatic ring, a positive ionizable and two hydrophobic regions; the pharmacophore of Raf-1 kinase is constituted by a hydrogen donor, a hydrogen acceptor, a hyd