Extra precision docking, free energy calculation and molecular dynamics simulation studies of CDK2 inhibitors

- Computational approach was applied to gain insight into selectivity for CDK2 inhibitors.
- These theoretical approaches reproduced the crystal structure precisely.
- The modification with substituents can show improved inhibitory activity against CDK2.

Molecular docking, free energy calculation and molecular dynamics (MD) simulation studies have been performed, to explore the putative binding modes of 3,5-diaminoindazoles, imidazo(1,2-b)pyridazines and triazolo(1,5-a) pyridazines series of Cyclin-dependent kinase (CDK2) inhibitors. To evaluate the effectiveness of docking protocol in flexible docking, we have selected crystallographic bound compound to validate our docking procedure as evident from root mean square deviations (RMSDs). We found different binding sites namely catalytic, inhibitory phosphorylation, cyclin binding and CKS-binding site of the CDK2 contributing towards the binding of these compounds. Moreover, correlation between free energy of binding and biological activity yielded a statistically significant correlation coefficient. Finally, three representative protein-ligand complexes were subjected to molecular dynamics simulation to determine the stability of the predicted conformations. The low value of the RMSDs between the initial complex structure and the energy minimized final average complex structure suggests that the derived docked complexes are close to equilibrium. We suggest that the phenylacetyl type of substituents and cyclohexyl moiety make the favorable interactions with a number of residues in the active site, and show better inhibitory activity to improve the pharmacokinetic profile of compounds against CDK2. The structure-based drug design strategy described in this study will be highly useful for the development of new inhibitors with high potency and selectivity.