Docking and three-dimensional quantitative structure-activity relationship analyses of imidazole and thiazolidine derivatives as Aurora A kinase inhibitors

摘要

Aurora A kinase is involved in the inactivation of apoptosis leading to ovarian, breast, colon, and pancreatic cancers. Inhibitors of Aurora A kinase promote aberrant mitosis resulting in arrest at a pseudo G1 state to induce mitotic catastrophe, ultimately leading to apoptosis. In this study, ligand-based and docking-based three-dimensional quantitative structure-activity relationship (3D-QSAR) analyses of imidazole and thiazolidine derivatives as potential Aurora A kinase inhibitors were performed. The results provided highly reliable and predictive 3D-QSAR comparative molecular similarity index analysis (CoMSIA) models with a cross-validated q(2) value of 0.768, non-cross-validated r(2) value of 0.983, and predictive coefficient value of 0.978. CoMSIA contour maps suggested that the NH and benzyl hydroxy groups in R-9, and the CO group in the thiazolidine ring and pyridine ring were important components for biological activity. The maps also suggest that the introduction of hydroxy groups at C-2 of the imino-phenyl ring, C-5 in the pyridine ring, or the substitution of the imino-phenyl ring for the imino-2-pyridine ring could be applied to enhance biological activity.