Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, China.
J Enzyme Inhib Med Chem. 2011 Jun;26(3):367-77. doi: 10.3109/14756366.2010.513331. Epub 2010 Sep 17.
Chemotypes comprising the d-annulated 1,3-dihydro-2H-1-benzazepin-2-one scaffold derived from the paullone structure were found to be potent vascular endothelial growth factor receptor 2 (VEGF-R2) kinase inhibitors. Three-dimensional quantitative structure-activity relationship (3D-QSAR) and docking studies were performed on a series of d-annulated benzazepinones with VEGF-R2 kinase inhibition activities. The comparative molecular field analysis and comparative molecular similarity indices analysis models using 32 molecules in the training set gave r(2)(cv) values of 0.811 and 0.769, r(2) values of 0.962 and 0.953, respectively. 3D contour maps generated from the two models revealed that the electron-withdrawing groups at R(1) and the bulky, electron-withdrawing as well as hydrogen bond donor groups at R(2) position are favourable; the bulky, hydrogen bond acceptor substituent at R(3) and the minor groups at R(4) position may benefit the potency. We have designed a series of novel VEGF-R2 inhibitors by utilizing the SAR results revealed in the present study, which were predicted with excellent potencies in the developed models. The results may aid in designing of potential VEGF-R2 inhibitors with better activities.
从保尔酮结构衍生而来的 d-稠合 1,3-二氢-2H-1-苯并氮卓-2-酮骨架的化学型被发现是强效的血管内皮生长因子受体 2（VEGF-R2）激酶抑制剂。对一系列具有 VEGF-R2 激酶抑制活性的 d-稠合苯并氮卓酮进行了三维定量构效关系（3D-QSAR）和对接研究。使用训练集中的 32 个分子的比较分子场分析和比较分子相似性指数分析模型分别给出了 0.811 和 0.769 的 r(2)(cv) 值，0.962 和 0.953 的 r(2) 值。两个模型生成的 3D 等高线图表明，R(1)处的吸电子基团和 R(2)处的大体积、吸电子和氢键供体基团是有利的；R(3)处的大体积、氢键受体取代基和 R(4)处的小基团可能有利于活性。我们利用本研究中揭示的 SAR 结果设计了一系列新型 VEGF-R2 抑制剂，这些抑制剂在开发的模型中具有优异的预测活性。这些结果可能有助于设计具有更好活性的潜在 VEGF-R2 抑制剂。
