Phosphorylation inhibition of cyclin dependent kinase 6/cyclin D complex with flavonoids using molecular dynamics simulations

Abstract

The cyclin dependent kinase (CDK) with an association partner cyclin are known to play an important role on the regulation of the cell cycle, apoptosis and transcription. The cyclin dependent kinase 6 (CDK6) with regulatory cyclin D (CDK6/v) drives cellular proliferation by phosphorylation reaction. To understand the CDK6 inhibitors i.e., flavonoids blocking the CDK6/Cyclin D at ATP binding pocket, MD simulations were performed on three flavonoid inhibitors complexed with CDK6/cyclin D in the four orientations, fisetin (FST-CDK6/v), apigenin (AGN-CDK6/v), chrysin (CHS_A-CDK6/v) and chrysin (CHS_B-CDK6/v). In all systems, the conserved strong H-bond at the 4-keto group of inhibitors via the backbone nitrogen of V101 was found. The 3'- and 4'-OH groups on the B ring were found to significantly increase in binding and inhibitory efficiency. The electrostatics interaction particularly the hydrogen bond formation, the vdW interactions with the I19, V27, F98, H100 and L152 were also found to increase in binding efficiency. The order of the predicted inhibitory affinities base on MM/PBSA approach of these four complexes are FST-CDK6/v > AGN-CDK6/v > CHS_A-CDK6/v ~ CHS_B-CDK6/v which is in good agreement with the experimental data (IC50). Moreover, the CHS_B-CDk6/v is the preferentially bind in the binding site.