吲哚衍生物类VEGFR-2酪氨酸激酶抑制剂的从头设计  

De novo Design of Indole Derivatives as VEGFR-2 Tyrosine Kinase Inhibitors

作　　者：康从民[1] 赵绪浩[1] 于玉琪 吕英涛[1] 

机构地区：[1]青岛科技大学化工学院,青岛266042

出　　处：《高等学校化学学报》2014年第3期550-554,共5页Chemical Journal of Chinese Universities

基　　金：国家自然科学基金(批准号:21072111;21272131);山东省自然科学基金(批准号:ZR2011BM015)资助~~

摘　　要：以血管内皮生长因子受体-2(VEGFR-2)酪氨酸激酶的晶体结构为基础,采用从头药物设计方法,设计了一系列吲哚类化合物,并用类药性和分子对接进行了筛选,最后得到10个对接能量较低的化合物分子,对具有最低结合能的化合物与VEGFR-2酪氨酸激酶的复合物进行了10 ns的分子动力学模拟,并对其结合模式进行了分析.这些化合物结构新颖,可能作为抗肿瘤的先导化合物或候选药物.本文结果为VEGFR-2酪氨酸激酶抑制剂的进一步改造、设计及合成提供了理论基础,并有助于开发高活性和高选择性的抗肿瘤药物.Protein tyrosine kinase（ PTK） is an especially important target for anticancer drug design due to its crucial role in the modulation of growth factor signaling. Vascular endothelial growth factor receptor-2 （VEGFR-2） tyrosine kinase plays a pivotal role in modulating angiogenesis, as well as the proliferation and migration of endothelium. Compounds that inhibit the activity of VEGFR-2 tyrosine kinase are potential chemo-therapeutics to treat tumors. In this study, based on the crystal structure of VEGFR-2 tyrosine kinase, de novo drug design was employed to develop a series of indole compounds. Absorption, distribution, metabolism, excretion and toxicity（ ADMET） and molecular docking were used to screen the designed compounds. Finally, ten molecules which have lower binding energy were obtained, a 10 ns molecular dynamics（ MD） calculation was performed to study the complex of the compound which has the lowest binding energy and VEGFR-2 tyrosine kinase, and then the binding models were analyzed. These new chemical entities could be lead com-pounds for anticancer. This result will provide theoretical basis for molecular structure improvement, molecular design, and molecular synthesis of VEGFR-2 tyrosine kinase inhibitors.

关 键 词：血管内皮生长因子受体-2 酪氨酸激酶抑制剂 从头药物设计 类药性 分子对接 

分 类 号：O621[理学—有机化学]