Abstract
Development of anticancer drugs targeting Aurora B, an important member of the serine/threonine kinases family, has been extensively focused on in recent years. In this work, by applying an integrated computational method, including comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), homology modeling and molecular docking, we investigated the structural determinants of Aurora B inhibitors based on three different series of derivatives of 108 molecules. The resultant optimum 3D-QSAR models exhibited (q2 = 0.605, r2pred = 0.826), (q2 = 0.52, r2pred = 0.798) and (q2 = 0.582, r2pred = 0.971) for MK-0457, GSK1070916 and SNS-314 classes, respectively, and the 3D contour maps generated from these models were analyzed individually. The contour map analysis for the MK-0457 model revealed the relative importance of steric and electrostatic effects for Aurora B inhibition, whereas, the electronegative groups with hydrogen bond donating capacity showed a great impact on the inhibitory activity for the derivatives of GSK1070916. Additionally, the predictive model of the SNS-314 class revealed the great importance of hydrophobic favorable contour, since hydrophobic favorable substituents added to this region bind to a deep and narrow hydrophobic pocket composed of residues that are hydrophobic in nature and thus enhanced the inhibitory activity. Moreover, based on the docking study, a further comparison of the binding modes was accomplished to identify a set of critical residues that play a key role in stabilizing the drug-target interactions. Overall, the high level of consistency between the 3D contour maps and the topographical features of binding sites led to our identification of several key structural requirements for more potency inhibitors. Taken together, the results will serve as a basis for future drug development of inhibitors against Aurora B kinase for various tumors.
Highlights
The Aurora kinases are a family of three highly homologous serine-threonine protein kinases (Aurora A, B and C) that play a critical role in regulating many of the processes that are pivotal to mitosis [1]
In order to develop an effective model with good prediction, a number of parameters, such as the cross-validated correlation coefficient (r2cv), non-cross-validated correlation coefficient (r2ncv), standard error estimate (SEE) and F-statistic values were taken into consideration
To further assess the stability and confidence of the derived comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models, bootstrapping analysis for 100 runs was applied to the compounds of the training set
Summary
The Aurora kinases are a family of three highly homologous serine-threonine protein kinases (Aurora A, B and C) that play a critical role in regulating many of the processes that are pivotal to mitosis [1]. Since it was discovered that Aurora kinases are aberrantly over-expressed in various tumor cells [2], there has been intense research in the area of identifying selective Aurora inhibitors as potential drugs; up to now more than 10 small molecules have entered clinical studies [1]. Aurora B is involved in ensuring chromosome segregation and alignment as part of the chromosomal passenger protein complex (CPC), which plays a key role in regulating progression through and completion of mitosis [4]. Some work showed that the depression of Aurora B kinase activity by small inhibitors could lead to a failure in cytokinesis and abnormal exit from mitosis, resulting in the endoreduplication, accumulation of polyploidy cells and apoptosis [5,6,7]
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