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


CONCLUSIONS
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.
Computational Science Center, Korea Institute of Science and Technology, Seoul, South Korea.
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Seung Joo
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D064127:Aurora Kinases; D016018:Least-Squares Analysis; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D021281:Quantitative Structure-Activity Relationship
D008024:Ligands; D047428:Protein Kinase Inhibitors; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases