Laboratory of Molecular Design and Drug Discovery, School of Basic Science, China Pharmaceutical University, Nanjing, China.
SAR QSAR Environ Res. 2012 Oct;23(7-8):705-30. doi: 10.1080/1062936X.2012.719541. Epub 2012 Sep 13.
Aurora kinases have emerged as attractive targets for the development of novel anti-cancer agents. A combined study of molecular docking, pharmacophore modelling and 3D-QSAR was performed on a series of imidazo [1, 2-a] pyrazines as novel Aurora kinase inhibitors to gain insights into the structural determinants and their structure-activity relationship. An ensemble of conformations based on molecular docking was used for PHASE pharmacophore studies. The developed best-fitted pharmacophore model was validated by diverse chemotypes of Aurora A kinase inhibitors and was consistent with the structural requirements for the docked binding mechanism. Subsequently, the pharmacophore-based alignment was used to develop PHASE and comparative molecular similarity indices analysis (CoMSIA) 3D-QSAR models. The best CoMSIA model showed good statistics (q (2 )= 0.567, r (2 )= 0.992), and the predictive ability of the model was validated using an external test set of 13 compounds giving a satisfactory prediction ([Formula: see text]). The 3D contour maps provided insight into the binding mechanism and highlighted key structural features that are essential to the inhibitory activity. Based on the PHASE and CoMSIA 3D-QSAR results, a set of novel Aurora A inhibitors were designed that showed excellent potencies.
极光激酶已成为开发新型抗癌药物的有吸引力的靶点。对一系列咪唑[1,2-a]吡嗪作为新型极光激酶抑制剂进行了分子对接、药效团建模和 3D-QSAR 的联合研究，以深入了解结构决定因素及其结构-活性关系。基于分子对接的构象集合用于 PHASE 药效团研究。开发的最佳拟合药效团模型通过多种 Aurora A 激酶抑制剂的化学型进行了验证，并且与对接结合机制的结构要求一致。随后，基于药效团的对齐用于开发 PHASE 和比较分子相似性指数分析（CoMSIA）3D-QSAR 模型。最佳 CoMSIA 模型显示出良好的统计学（q （2）= 0.567，r （2）= 0.992），并且使用 13 个化合物的外部测试集验证了模型的预测能力，得到了令人满意的预测（[公式：见文本]）。3D 等高线图提供了对结合机制的深入了解，并突出了对抑制活性至关重要的关键结构特征。基于 PHASE 和 CoMSIA 3D-QSAR 结果，设计了一组新型极光 A 抑制剂，表现出优异的效力。
