Identification of natural inhibitors against CDK6 target using pharmacophore-based screening, molecular docking, molecular dynamic simulations, and quantitative electrostatic potential analysis maps: A comprehensive study.

In this study, a mixing of pharmacophore-based screening, molecular docking virtual screening, molecular dynamic simulation, and quantitative electrostatic potential map analysis was performed at the binding cavity of the CDK6 target. The generated pharmacophore model has five features. After the validation of the model, a virtual screening process was conducted on the natural coconut database. The screened ligands were selected for molecular docking virtual screening. 800 ligands were docked, and the ligands were selected based on the docking scores and main interactions. The first four top-ranked compounds in the docking process were selected for the assessment of the stability of the interactions and binding site cavity through molecular dynamic simulation. Finally, MM-PBSA and electrostatic potential surface analyzes were performed on the compounds A-D and the standard and co-crystalized compounds. Compound A reveals superior features, including binding affinity, stability and binding-free energy compared to compound palbociclib ligand. These analyses lead to a deeper insight into the stability and charge distribution of selected hit compounds for further optimization of the natural ligands to achieve novel natural selective CDK6 inhibitors.