Molecular insights of benzodipyrazole as CDK2 inhibitors: combined molecular docking, molecular dynamics, and 3D QSAR studies

Abstract

Benzodipyrazoles have been previously evaluated for their in vitro CDK2 inhibitory activity. In the current investigation, we identified a six-feature common pharmacophore model (AADDRR.33) which is predicted to be responsible for CDK2 inhibition. An efficient 3D QSAR (r²= 0.98 and q²= 0.82) model was also constructed by employing PLS regression analysis. From the molecular docking studies, we examined the binding patterns of compound 7aa with the target protein and also calculated the binding energy using MM-GBSA calculations. Three hydrogen bonds with Lys 33, Glu 81, and Leu 83 are conserved even after 1000 ps run in a molecular dynamics simulation. We identified the slight displacement in bond lengths and the conformational changes occurred during the dynamics. The results also elucidated the protein residue–ligand interaction fractions which clearly explained the involvement of non-H-bond interactions.

• CDKs
• benzodipyrazoles
• MM-GBSA
• molecular dynamics
• QSAR

Acknowledgements

The authors would like to thank Dr. Yamini Lingala, Department of Chemistry, Nijam College – Osmania University, Hyderabad, India, and Mr. Ravi Raja Merugu, Department of Bioinformatics, SRM University, Tamil Nadu, India, for their great support and providing the necessary tools to carry out the simulation studies.

Declaration of interest

The authors report no conflicts of interest.

Supplementary data available online

Supplementary Table 1