An in silico approach to discover the best molecular modeling strategy for designing novel CDK4 inhibitors.

Designing of new potential specific inhibitors for CDK4 is very important in cancer therapy. The imperative features that can inhibit CDK4 were identified and refined by docking under standard precision mode, extra precision mode, extra precision mode with core constraints, and induced fit using extra precision protocol. Statistically significant correlation was observed when docking experiments in the extra precision mode carried out by applying core constraints in the ligand molecule which forms two specific hydrogen bonds with Val 96 of CDK4. Importance of solvent molecule was understood by molecular dynamic simulation studies. The presence of a water molecule which forms a hydrogen bond with Asp158 increased the binding affinity between the ligand and CDK4. Hydrogen bonding interactions, pi-pi stacking interactions, and salt bridge formation were the key interactions contributing to the increased inhibitory value. All these findings were supported by the high correlation between pIC50 and glide emodel values. Binding energy determinations under various conditions also support these findings. Thus, extra precision docking with ligand constraints through the insertion of water molecule effectively classified the actives and inactives of given set of molecules and can be used for virtual screening of new molecules for promising biological activity.