Structural studies of B-type Aurora kinase inhibitors using computational methods

Abstract

To characterize the structural features of quinazoline-based Aurora B inhibitors that influence its inhibitor activity. Two geometrical methods, Method 1 and Method 2, were used to develop the 3D-QSAR models. The most active ligand was used as the template for the alignment of all the ligands in Method 1, and a conformer of the cocrystal ligand was used as the template for the alignment of all the ligands in Method 2. The models suggest that highly active ligands can be designed by varying the R1 substituent at position 7 of the quinazoline ring with positively charged, bulky, hydrophobic groups, while bulky and hydrophobic groups around the thiazole ring are desirable for higher activity. This study emphasizes that the bioactive conformer is rather different from the minima. The steric, electrostatic, and hydrophobic field effects contribute to its inhibitory activity.