Molecular docking simulation studies of curcumin and its derivatives as cyclin-dependent kinase 2 inhibitors

Abstract

Objectives: Cyclin-dependent kinase 2 (CDK2) is a protein that plays a role in regulating the cell cycle and its overexpression contributes to uncontrolled cell proliferation. Inhibition of CDK2 is known to be a mechanism of action of various anti-cancer drugs. Curcumin is an active compound of Curcuma longa and it has been reported to inhibit the activity of cyclin D, cyclin E, CDK2, CDK4, and CDK6. This study aimed to design more active curcumin derivatives as anticancer drugs by targeting CDK2 through a molecular modeling approach. Materials and Methods: The molecular modeling approach consists of receptor and ligand preparation, method validation, pharmacophore modeling, and docking simulation. Results: The results of the molecular docking simulation show that the free bonding energy (∆G) of curcumin and kurkumod 23 and 24 (the best modification of curcumin) are-7.80,-9.15, and-9.36 kcal/mol, respectively. The hydrogen interaction between kurkumod 23 and 24 with CDK occurred on Lys33 residue, which is considered a potential interaction site for CDK2 inhibitor compounds. Pharmacophore modeling showed that kurkumod 23 and 24 have pharmacophore-fit values of 45.20% and 47.26%, respectively. Conclusion: The results of this study indicate that kurkumod 23 and 24 are the best and most potent modifications of curcumin as CDK2 antagonist, based on the interactions that occur between these two derivatives with amino acid residues from the CDK2 receptor.