Acta Pharmacologica Sinica (2010) 31: 244–258; doi: 10.1038/aps.2009.188

¹Department of Cellular Molecular Medicine and Research Center for Resistant Cells, College of Medicine, Chosun University, Gwangju 501-759, South Korea; ²Computational Science Center, Future Fusion Technology Division, Korea Institute of Science and Technology, PO Box 131, Seoul 130-650, South Korea; ³Korea University of Science and Technology, 52, Eoeun-dong, Yuseong-gu, Daejon 305–333, South Korea

Aim: To characterize the structural features of quinazoline-based Aurora B inhibitors that influence its inhibitor activity. 

Methods: 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. 

Results: 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. 

Conclusion: 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.

Keywords: 3D-QSAR; drug design; CoMFA; CoMSIA; Aurora B; kinase