Targeting Overexpressed Cyclin Dependent Kinase 1 (CDK1) in Human Cancers: Kamalachalcone A Emerged as Potential Inhibitor of CDK1 Kinase Through in Silico Docking Study

Abstract

Background: CDK1 gene located in human chromosome 10, encodes CDK1 (tyrosine) kinase, overexpressed in multiple cancer cells. Upon phosphorylation of tyrosine kinases by adenosine triphosphate, CDK1 kinase is activated in cell cycle progression. Nonetheless, CDK1 kinase excessively partakes in the development and prognosis of specific types of aggressive cancers. Therefore, CDK1 kinase inhibition therapy is a primary target for the treatment of explicitly expressed CDK1 kinase cancers. At present, dinaciclib is the only FDA approved orphan CDK1 kinase inhibitor drug in the treatment of cancers. In molecular docking study, kamalachalcone A with significant higher binding energy competitively bound to the active receptor site of CDK1 kinase, as comparable to dinaciclib. In this framework, kamalachalcone A could emerge as a potential candidate for restricting the over expression of CDK1 kinase in multiple cancers. Objective: The present study aimed to compare the inhibitory activity of dinaciclib (CDK1 kinase inhibitor drug) with kamalachalcone A, a novel chalcone found in kamala dye. Methods: Dinaciclib and kamalachalcone A were docked on human CDK1 kinase 3D structure in molecular docking using AutoDock 4.2.6, MGL tools and molecular dynamic studies with iMOD server (iMODS). Results: These studies revealed that kamalachalcone A was a competitive CDK1 kinase inhibitor alike dinaciclib. The docking results suggested binding site similarities of dinaciclib and kamalachalcone A. The binding energies of docked dinaciclib and kamalachalcone A complexes with CDK1 kinase were -8.52 kcal/mol and -12.81 kcal/mol, respectively. The docking results were substantiated by molecular simulation studies with iMODS. Conclusion: The in silico docking simulation of dinaciclib and kamalachalcone A suggested that kamalachalcone A is likewise a competitive CDK1 kinase inhibitor.