The binding efficiencies of flavonoids against the CDK6/cyclin D complex were mainly through the electrostatic (especially the H-bond force) and vdW interactions with residues ILE19, VAL27, ALA41, GLU61, PHE98, GLN103, ASP163 and LEU152. For all six flavonoids, the 3’-OH and 4’-OH of B-ring were found to be favorable for hydrogen bond formation, but the 3-OH on the C-ring and 5-OH on the A-ring were unfavorable, which were confirmed by the MD simulation results of the test molecule, 3’, 4’, 7-trihydroxyflavone (M15). To understand the binding behavior of flavonoids that inhibit the active CDK6, molecular dynamics (MD) simulations were performed on six inhibitors, chrysin (M01), fisetin (M03), galangin (M04), genistein (M05), quercetin (M06) and kaempferol (M07), complexed with CDK6/cyclin D. Analysis of per residue decomposition energies suggested that, compared with other residues as displayed in Fig 7, residues ILE19, VAL27, ALA41, GLU61, ASP163, LEU152, as well as two residues in the hinge region (including PHE98, GLN103) present lower values, and may play crucial roles in the binding of flavonoids.įlavonoids, a class of natural compounds with variable phenolic structures, have been found to possess anti-cancer activities by modulating different enzymes and receptors like CDK6. Previous results on H-bond studies of CDK6/cyclin D with seven flavonoids (as displayed in Figs 3 and 7) show that GLU61, ASP163, the hinge residue VAL101and the gatekeeper residue ASP104 are important for the formation of H-bonds, which is in accordance with the Deciphering the binding behavior of flavonoids-CDK6/cyclin D complexes previous reports on CDK6/cyclin D as researched by W Khuntawee et al. The crucial amino acids contributing to the binding were protein residues which had intermolecular interactions with ligand, and the detailed results of per residue decomposition energy analysis for each flavonoid were displayed in Fig 7. To further analyzing the flavonoids-CDK6/cyclin D interactions, per residue decomposition approach was employed to quantify the role of identified crucial amino acids. The obtained results are useful as the basic information for the further design of potent anticancer drugs specifically targeting the CDK6 enzyme. In addition, CHS preferentially binds to the active CDK6 in a different orientation to FST and AGN but similar to its related analog, deschloro-flavopiridol. On the basis of the docking calculation and MM-PBSA method, the order of the predicted inhibitory affinities of these three inhibitors toward the CDK6/cycD was FST > AGN > CHS, which is in good agreement with the experimental data. Besides the electrostatic interactions, especially through hydrogen bond formation, the van der Waals (vdW) interactions with the I19, V27, F98, H100, and L152 residues of CDK6 are also important factors in the binding efficiency of flavonoids against the CDK6/cycD complex. The 3'- and 4'-OH groups on the flavonoid phenyl ring and the 3-OH group on the benzopyranone ring of inhibitor were found to significantly increase the binding and inhibitory efficiency. For all three inhibitors, including both CHS orientations, the conserved interaction between the 4-keto group of the flavonoid and the backbone V101 nitrogen of CDK6 was strongly detected.
To understand the flavonoids that inhibit the CDK6/cycD functions, molecular dynamics simulations (MDSs) were performed on three inhibitors, fisetin (FST), apigenin (AGN), and chrysin (CHS), complexed with CDK6/cycD, including the two different binding orientations of CHS: FST-like (CHS_A) and deschloro-flavopiridol-like (CHS_B). The CDK6 complex with cyclin D (CDK6/cycD) drives cellular proliferation by phosphorylation of specific key target proteins. The cyclin dependent kinases (CDKs), each with their respective regulatory partner cyclin that are involved in the regulation of the cell cycle, apoptosis, and transcription, are potentially interesting targets for cancer therapy.
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