3D-QSAR and Molecular Docking Studies on Derivatives of MK-0457, GSK1070916 and SNS-314 as Inhibitors against Aurora B KinaseReportar como inadecuado




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1

School of Chemical Engineering, Dalian University of Technology, Dalian, Liaoning, 116012, China

2

Center of Bioinformatics, Northwest A&F University, Yangling, Shaanxi, 712100, China

3

Lab of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Graduate School of the Chinese Academy of Sciences, Dalian, Liaoning, 116023, China





*

Author to whom correspondence should be addressed.



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. View Full-Text

Keywords: Aurora B; drug design; 3D-QSAR; CoMFA; CoMSIA; molecular docking; homology modeling Aurora B; drug design; 3D-QSAR; CoMFA; CoMSIA; molecular docking; homology modeling





Autor: Baidong Zhang 1, Yan Li 1,* , Huixiao Zhang 2 and Chunzhi Ai 3

Fuente: http://mdpi.com/



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