Chapter Four Controlling cell proliferation by targeting cyclin-dependent kinase 6 using drug repurposing approach

Abstract

Cyclin-dependent kinase 6 (CDK6) is an essential kinase in cell cycle progression, which is a viable target for inhibitors in various malignancies, including breast cancer. This study aimed to virtually screen efficient compounds as new leads in treating breast cancer using a drug repurposing approach. Apoptosis regulatory compounds were taken from the seleckchem database. Molecular docking experiments were carried out in the presence of abemaciclib, a routinely used FDA drug. Compared to conventional drugs, the two compounds demonstrated a higher binding affinity for CDK6. Compounds (N-benzyl-6-[(4-hydroxyphenyl)methyl]-8-(naphthalen-1-ylmethyl)-4,7-dioxo-3,6,9,9a-tetrahydro-2H-pyrazino[1,2-a]pyrimidine-1-carboxamide) and (1′-[4-[1-(4-fluorophenyl)indol-3-yl]butyl]spiro[1H-2-benzofuran-3,4′-piperidine]) were discovered to have an inhibitory effect against CDK6 at −8.49 and −6.78kcal/mol, respectively, compared to −8.09kcal/mol of the control molecule, the interacting residues of these two new compounds were found to fall within the binding site of the CDK6 molecule. Both compounds exhibited equal ADME features compared with abemaciclib and would be well distributed and metabolized by the body with an appropriate druglikeness range. Lastly, molecular dynamics was initiated for 200ns for the selected potent inhibitors and abemaciclib as complexed with CDK6. The RMSD, RMSF, Rg, H-Bond interactions, SASA, PCA, FEL, and MM/PBSA analysis were performed for the complexes to assess the stability, fluctuations, radius of gyration, hydrogen bond interaction, solvent accessibility, essential dynamics, free energy landscape, and MM/PBSA. The selected two compounds are small molecules in the appropriate druglikeness range. The results observed in molecular docking and molecular dynamics simulations were most promising for two compounds, suggesting their potent inhibitory effect against CDK6. We propose that these candidate compounds can undergo in vitro validation and in vivo testing for their further use against cancer.