A definitive pharmacophore modelling study on CDK2 ATP pocket binders: tracing the path of new virtual high-throughput screenings

Cyclin Dependent Kinases-2 (CDK2) are members of serine/threonine protein kinases family. They play an important role in the regulation events of the eukaryotic cell division cycle, especially during the G1 to S phase transition. Experimental evidences indicate that excessive expression of CDK2s should cause abnormal cell cycle regulation. Therefore, since long time, CDK2s have been considered potential therapeutic targets for cancer therapy. In this work, one-hundred and forty-nine complexes of inhibitors bound in the CDK2-ATP pocket were submitted to short MD simulations (10ns) and free energy calculation. Comparison with experimental data (Ki, Kd and pIC50) revealed that short simulations are exhaustive to examine the crucial ligand-protein interactions within the complexes. Information collected on MD simulations of protein-ligand complexes have been used to perform a molecular modelling approach that incorporates flexibility into structure-based pharmacophore modelling (Common Hits Approach, CHA). The high number of pharmacophore models resulting from the MD simulation was thus reduced to a few representative groups of pharmacophore models. The performance of the models have been assessed by using the ROC curves analysis. This definitive set of validated pharmacophore models could be used to screen in-house and/or commercial datasets for detection of new CDK-2 inhibitors. We provide the models to all the researchers involved in this field.