title: Docking and three-dimensional quantitative structure-activity relationship analyses of imidazole and thiazolidine derivatives as Aurora A kinase inhibitors.
abstract: 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 q2value of 0.768, non-cross-validated r2value of 0.983, and predictive coefficient [Formula: see text] value of 0.978. CoMSIA contour maps suggested that the NH and benzyl hydroxy groups in R9, 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 C2of the imino-phenyl ring, C5in the pyridine ring, or the substitution of the imino-phenyl ring for the imino-2-pyridine ring could be applied to enhance biological activity.
authors.affiliation: College of Pharmacy, Chung-Ang University, Heukseok-Dong, Dongjak-Gu, Seoul , 156-756, Korea. chaeukim@cau.ac.kr.
authors.forename: Chaeuk
authors.initials: C
authors.lastname: Im
mesh_terms: D064096:Aurora Kinase A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites / Q000502:physiology; D021621:Imaging, Three-Dimensional / Q000379:methods; D007093:Imidazoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D008958:Models, Molecular; D062105:Molecular Docking Simulation / Q000379:methods*; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D053778:Thiazolidines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D053778:Thiazolidines; C029899:imidazole; D064096:Aurora Kinase A
keywords: 3D-QSAR; Aurora A kinase; CoMSIA; Docking; Inhibitors