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Molecular dynamic behavior and binding affinity of flavonoid analogues to the cyclin dependent kinase 6/cyclin D

Wasinee Khuntawee1, Thanyada Rungrotmongkol, Supot Hannongbua

  • 1Computational Chemistry Unit Cell, Department of Chemistry, Faculty of Science, Chulalongkorn University, 254 Phayathai Road, Bangkok 10330, Thailand.

Journal of Chemical Information and Modeling
|December 17, 2011
PubMed

Insights

Flavonoids like fisetin, apigenin, and chrysin inhibit CDK6/cyclin D, a key driver of cell proliferation. Molecular simulations reveal key interactions and binding affinities, guiding the design of new anticancer drugs targeting CDK6.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Cyclin-dependent kinases (CDKs) regulate crucial cellular processes like the cell cycle and apoptosis.
  • The CDK6/cyclin D complex promotes cellular proliferation and is a potential cancer therapy target.
  • Flavonoids are natural compounds with potential therapeutic properties, including anticancer activity.

Purpose of the Study:

  • To investigate the inhibitory mechanisms of three flavonoids (fisetin, apigenin, chrysin) against the CDK6/cyclin D complex.
  • To understand the molecular interactions and binding orientations of these flavonoids with CDK6/cyclin D.
  • To provide insights for designing novel anticancer drugs targeting CDK6.

Main Methods:

  • Molecular dynamics simulations (MDSs) were employed to study the interactions between CDK6/cyclin D and the inhibitors.
  • Docking calculations and the MM-PBSA method were used to predict binding affinities.
  • Analysis of conserved interactions, hydrogen bonding, and van der Waals forces was performed.

Main Results:

  • A conserved interaction between the flavonoid 4-keto group and CDK6 backbone V101 was observed for all inhibitors.
  • Specific hydroxyl groups (3'-OH, 4'-OH, 3-OH) significantly enhanced binding and inhibitory efficiency.
  • The predicted inhibitory order (FST > AGN > CHS) aligned with experimental data, with CHS showing a distinct binding orientation.

Conclusions:

  • Flavonoids exhibit inhibitory effects on CDK6/cyclin D through specific electrostatic and van der Waals interactions.
  • The binding mode and affinity are influenced by the chemical structure of the flavonoids.
  • These findings offer a foundation for developing potent, CDK6-specific anticancer agents.

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