Abstract
Aurora kinases have emerged as attractive targets for the design of anticancer drugs. 3D-QSAR (comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA)) and Surflex-docking studies were performed on a series of pyrrole-indoline-2-ones as Aurora A inhibitors. The CoMFA and CoMSIA models using 25 inhibitors in the training set gave r2cv values of 0.726 and 0.566, and r2 values of 0.972 and 0.984, respectively. The adapted alignment method with the suitable parameters resulted in reliable models. The contour maps produced by the CoMFA and CoMSIA models were employed to rationalize the key structural requirements responsible for the activity. Surflex-docking studies revealed that the sulfo group, secondary amine group on indolin-2-one, and carbonyl of 6,7-dihydro-1H-indol-4(5H)-one groups were significant for binding to the receptor, and some essential features were also identified. Based on the 3D-QSAR and docking results, a set of new molecules with high predicted activities were designed.
Highlights
The Aurora kinases are a family of highly conserved serine/threonine protein kinases that play a key role in regulating many pivotal processes of mitosis and completion of cell division [1,2,3,4,5]
Aurora A is involved in centrosome maturation and separation, bipolar spindle assembly, and mitotic entry, while Aurora B is essential for accurate chromosome segregation and cytokinesis [7]
comparative molecular field analysis (CoMFA) model, partial least squares (PLS) regression produced a excellent cross-validated correlation coefficient (r2cv) of 0.726 (>0.5) with an optimized component of 6, which suggesting that the model is reliable and it should be a useful tool for predicting the IC50 values
Summary
The Aurora kinases are a family of highly conserved serine/threonine protein kinases that play a key role in regulating many pivotal processes of mitosis and completion of cell division [1,2,3,4,5]. The two major Aurora kinases, Aurora A and Aurora B, play distinct roles in mitosis, though they are very closely related in kinase domain sequence (71% identical) and have the identical residues lining the binding pocket for the ATP adenine ring [6]. Targeted inhibition of Aurora A has become an attractive therapeutic strategy in cancer therapy, and more than 10 Aurora inhibitors have entered early clinical assessment [11,12]
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