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

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 (r(2 )= 0.98 and q(2 )= 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.