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论文类型：期刊论文

发表时间：2012-03-01

发表刊物：JOURNAL OF MOLECULAR MODELING

收录刊物：SCIE、Scopus

卷号：18

期号：3

页面范围：1107-1122

ISSN号：1610-2940

关键字：Aurora-A; Inhibitor; 3D-QSAR; CoMFA; CoMSIA; Molecular docking

摘要：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.