QSAR studies on imidazopyrazine derivatives as Aurora A kinase inhibitors

Abstract

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 (). 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.

Keywords:

• 3D-QSAR
• pharmacophore
• CoMSIA
• docking
• Aurora A kinases
• PHASE

Acknowledgments

The work was supported financially by the National Natural Science Foundation of China (30973609) and Qing Lan Project of Jiangsu Province, China.