title: Probing the structural requirements of A-type Aurora kinase inhibitors using 3D-QSAR and molecular docking analysis.
abstract: Aurora-A, the most widely studied isoform of Aurora kinase overexpressed aberrantly in a wide variety of tumors, has been implicated in early mitotic entry, degradation of natural tumor suppressor p53 and centrosome maturation and separation; hence, potent inhibitors of Aurora-A may be therapeutically useful drugs in the treatment of various forms of cancer. Here, we report an in silico study on a group of 220 reported Aurora-A inhibitors with six different substructures. Three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were carried out using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques on this series of molecules. The resultant optimum 3D-QSAR models exhibited an r                                                     (cv)                                      (2)                          value of 0.404-0.582 and their predictive ability was validated using an independent test set, ending in r                                                     (pred)                                      (2)                          0.512-0.985. In addition, docking studies were employed to explore these protein-inhibitor interactions at the molecular level. The results of 3D-QSAR and docking analyses validated each other, and the key structural requirements affecting Aurora-A inhibitory activities, and the influential amino acids involved were identified. To the best of our knowledge, this is the first report on 3D-QSAR modeling of Aurora-A inhibitors, and the results can be used to accurately predict the binding affinity of related analogues and also facilitate the rational design of novel inhibitors with more potent biological activities.
authors.affiliation: Center of Bioinformatics, Northwest A&F University, Yangling, Shaanxi 712100, China.
authors.forename: Hui-Xiao
authors.initials: HX
authors.lastname: Zhang
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Xia
authors.initials: X
authors.lastname: Wang
authors.forename: Yong-Hua
authors.initials: YH
authors.lastname: Wang
mesh_terms: D064127:Aurora Kinases; D003198:Computer Simulation; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases