QSAR studies on imidazopyrazine derivatives as Aurora A kinase inhibitors

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.