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甲基苯甲酸为母核结构,具有较好的预测活性。
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 hydrophobic regions and an aromatic ring.There are some similarities between the two pharmacophores.After analysis of the constructions of these two pharmacophores,some new aminomethylbenzoic acid derivatives with good forecasting activity against both of FTase and Raf-1 kinase were designed with these new pharmacophore models.
出处
《药学学报》
CAS
CSCD
北大核心
2011年第2期170-178,共9页
Acta Pharmaceutica Sinica
基金
国家"重点新药创制"科技重大专项(2009AX09301-014)
