Molecular docking-based 3D-QSAR studies of pyrrolo[3,4-c]pyrazole derivatives as Aurora-A inhibitors

Abstract

In recent years, Aurora kinases have been highlighted as attractive targets for the development of novel anti-cancer agents. To find the correlation between Aurora-A and its inhibitors, structure-based 3D-quantitative structure–activity relationship (QSAR) models were performed on a series of pyrrolo[3,4-c]pyrazole derivatives with comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods. Based on the docking results, predictive 3D-QSAR models were established, with cross-validated coefficient values () up to 0.667 for CoMFA and 0.664 for CoMSIA, respectively. Furthermore, the CoMFA and CoMSIA models were mapped back to the binding sites of Aurora-A, which could get a better understanding of vital interactions between the inhibitors and the kinase. Ligands binding in the ATP pocket and the hydrogen bonds with Ala213 and Glu211 were found to be crucial for the potent ligand binding and kinases selectivity. Therefore, these results demonstrated the power of combining the docking/QSAR approach to explore the probable binding conformations of compounds at the active sites of the protein, and further provided useful information for designing new compounds that showed very low binding free energy against the Aurora-A kinase, and which had been shifted for further experimental assay studies.

Keywords:

• pyrrolo[3,4-c]pyrazole derivatives
• 3D-QSAR
• molecular docking
• CoMFA
• CoMSIA