Role of Interactions and Volume Variation in Discriminating Active and Inactive Forms of Cyclin-Dependent Kinase-2 Inhibitor Complexes

Molecular recognition process occurs through various non‐bonded interactions in protein–ligand complexes. Analysis and visualization of interactions in a set of protein–ligand complexes provide insight for structure‐based drug design. In the present study, we have made a comprehensive analysis on similarities and differences observed in hydrophobic interactions and hydrogen bond interactions of 170 X‐ray crystal structures of active and inactive cyclin‐dependent kinase‐2 (CDK‐2) ligand complexes obtained from the Protein Data Bank. We have also systematically analyzed variation of protein binding cavity volume (PCV) and ligand volume (LV) in CDK‐2 ligand complexes. Hierarchical clustering of interaction patterns of CDK‐2 ligands have been carried out in active and inactive forms. In PCV and LV analysis, PCV variation was observed to be high for inactive conformation and less for active conformation; the latter was found to bind ligands with higher volume. Further, correlation of interactions, PCV, and LV with the binding affinity was analyzed in active and inactive forms. Analysis of interactions and volume changes revealed the marked difference in CDK‐2 active and inactive conformations. In conclusion, this study highlights the importance of considering inactive conformation in the docking and scoring methods to attain selectivity and potency. In CDK‐2 ligand complexes, binding affinity had high correlation with interactions and volume changes [protein binding cavity volume (PCV) and ligand volume (LV)] in active and inactive conformation respectively. Consideration of inactive conformation in docking and scoring studies may result in screening of highly selective and potent inhibitors.