Kang Cong-Min, Liu Dong-Qing, Zhao Xu-Hao, Dai Ying-Jie, Cheng Jia-Gao, Lv Ying-Tao
a College of Chemical Engineering, Qingdao University of Science and Technology , Qingdao , P.R. China and.
b Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology , Shanghai , P.R. China.
J Recept Signal Transduct Res. 2016;36(1):103-9. doi: 10.3109/10799893.2015.1049364. Epub 2015 Sep 29.
The three-dimensional quantitative structure-activity relationships (3D-QSAR) were established for 30 oxindole derivatives as vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase inhibitors by using comparative molecular field analysis (CoMFA) and comparative similarity indices analysis comparative molecular similarity indices analysis (CoMSIA) techniques. With the CoMFA model, the cross-validated value (q(2)) was 0.777, the non-cross-validated value (R(2)) was 0.987, and the external cross-validated value ([Formula: see text]) was 0.72. And with the CoMSIA model, the corresponding q(2), R(2) and [Formula: see text] values were 0.710, 0.988 and 0.78, respectively. Docking studies were employed to bind the inhibitors into the active site to determine the probable binding conformation. The binding mode obtained by molecular docking was in good agreement with the 3D-QSAR results. Based on the QSAR models and the docking binding mode, a set of new VEGFR-2 tyrosine kinase inhibitors were designed, which showed excellent predicting inhibiting potencies. The result revealed that both QSAR models have good predictive capability to guide the design and structural modification of homologic compounds. It is also helpful for further research and development of new VEGFR-2 tyrosine kinase inhibitors.
采用比较分子场分析（CoMFA）和比较相似性指数分析（CoMSIA）技术，对30种吲哚酮衍生物作为血管内皮生长因子受体-2（VEGFR-2）酪氨酸激酶抑制剂建立了三维定量构效关系（3D-QSAR）。在CoMFA模型中，交叉验证值（q(2)）为0.777，非交叉验证值（R(2)）为0.987，外部交叉验证值（[公式：见原文]）为0.72；在CoMSIA模型中，相应的q(2)、R(2)和[公式：见原文]值分别为0.710、0.988和0.78。采用对接研究将抑制剂与活性位点结合，以确定可能的结合构象。通过分子对接获得的结合模式与3D-QSAR结果吻合良好。基于QSAR模型和对接结合模式，设计了一组新的VEGFR-2酪氨酸激酶抑制剂，其预测抑制活性优异。结果表明，两种QSAR模型均具有良好的预测能力，可指导同源化合物的设计和结构修饰，也有助于新型VEGFR-2酪氨酸激酶抑制剂的进一步研发。
