Deciphering the binding behavior of flavonoids to the cyclin dependent kinase 6/cyclin D complex

<div><p>Flavonoids, 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. 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. 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). 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. The order of binding affinities of these flavonoids toward the CDK6/cyclin D was M03 > M01 > M07 > M15 > M06 > M05 > M04. It is anticipated that the binding features of flavonoid inhibitors studied in the present work may provide valuable insights for the development of CDK6 inhibitors.</p></div

Average MM-PBSA free energies (kcal/mol) of flavonoid-CDK6/cyclin D complexes.

<p>Average MM-PBSA free energies (kcal/mol) of flavonoid-CDK6/cyclin D complexes.</p

<i>Per</i> residue decomposition energies (Δ<i>G</i>bind^residue) of crucial amino acids in various inhibitors.

<p><i>Per</i> residue decomposition energies (Δ<i>G</i>bind^residue) of crucial amino acids in various inhibitors.</p

Deciphering the binding behavior of flavonoids to the cyclin dependent kinase 6/cyclin D complex - Fig 6

<p>(a) Chemical structure of M15; (b) RMSD profile of M15-CDK6/cyclin D complex; (c) M15-CDK6/cyclin D interaction plot; (d) The number of hydrogen bonds during the MD simulation.</p

The molecular docking results of flavonoids.

<p>The molecular docking results of flavonoids.</p

The major classes of flavonoids and the chemical structures of representative molecules that are discussed in this article.

<p>The major classes of flavonoids and the chemical structures of representative molecules that are discussed in this article.</p

Average MM-PBSA free energies (kcal/mol) of flavonoid-CDK6/cyclin D complexes.

<p>Average MM-PBSA free energies (kcal/mol) of flavonoid-CDK6/cyclin D complexes.</p

The weak interaction analysis in flavonoid-CDK6/cyclin D complex.

<p>The weak interaction analysis in flavonoid-CDK6/cyclin D complex.</p

RMSD profiles of six simulated systems.

<p>RMSD profiles of six simulated systems.</p

Flavonoid-CDK6/cyclin D interaction plots generated by LigPlot+[46] and the stereo view of flavonoid-CDK6/cyclin D interaction.

<p>Flavonoid-CDK6/cyclin D interaction plots generated by LigPlot+[<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0196651#pone.0196651.ref046" target="_blank">46</a>] and the stereo view of flavonoid-CDK6/cyclin D interaction.</p