Abstract
CDK2/cyclin A has appeared as an attractive drug targets over the years with diverse therapeutic potentials. A computational strategy based on comparative molecular fields analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) followed by molecular docking studies were performed on a series of 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives as potent CDK2/cyclin A inhibitors. The CoMFA and CoMSIA models, using 38 molecules in the training set, gave r2cv values of 0.747 and 0.518 and r2 values of 0.970 and 0.934, respectively. 3D contour maps generated by the CoMFA and CoMSIA models were used to identify the key structural requirements responsible for the biological activity. Molecular docking was applied to explore the binding mode between the ligands and the receptor. The information obtained from molecular modeling studies may be helpful to design novel inhibitors of CDK2/cyclin A with desired activity.
Highlights
All physiological processes and a majority of human diseases involve protein phosphorylation
A considerable amount of investigations have been carried out to develop inhibitors that target CDK2/cyclin A for treating cancer, and several CDK2/cyclin A inhibitors have been under clinical evaluation [10]. 3D-QSAR and docking approaches have emerged as one of the most powerful tools in ligand based drug design strategies [11,12]
Model of a series of 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives was generated using leave-one-out Partial Least Squares (PLS) analysis with an optimized component of 5 to give a good cross-validated correlation coefficient (r2cv) of 0.747 (>0.5), which suggesting that the model should be a reasonable tool for predicting the IC50 values
Summary
All physiological processes and a majority of human diseases involve protein phosphorylation. It was revealed in previous studies that the inhibitors of these CDKs/cyclins were down-regulated in most of the cancer cells [9,10]. 3D-QSAR and docking approaches have emerged as one of the most powerful tools in ligand based drug design strategies [11,12]. They have been used to develop efficient models for identifying CDK2/cyclin A inhibitors [13,14]. A series of compounds containing 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline that have potent CDK2/cyclin A inhibitory activities were reported by literature [15]. Molecular modeling studies of these 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives were performed by using 3D-QSAR and docking approaches. The constructed models can help in understanding the structure-activity relationship of these compounds but can serve as a useful guide for the design of new inhibitors with desired potencies
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