Identification of natural marine compounds as potential inhibitors of CDK2 using molecular docking and molecular dynamics simulation approach.

The multifunctional enzyme cyclin-dependent kinase 2 (CDK2) protein is essential for cell proliferation, transcription and modulation of the cell cycle. There is a dysfunction that is connected to various diseases, such as cancer, making it an important treatment target in oncology and beyond. The goal of this study is to identify novel CDK2 ATP binding site inhibitors using in silico drug designing. To find competitive inhibitors for the ATP site, molecular docking, molecular dynamics (MD) simulation and free-binding energy calculations were used. Natural compounds retrieved from marine sources (fungi and algae) were docked against protein, and the best-binding compounds were further evaluated using MD simulations. LIG1, LIG2 and LIG3 (ΔG PB = -19.98, -15.82 and -12.98 kcal/mol, respectively) were placed in the top positions based on their overall binding energy calculated using MMPBSA approach. Stability of the complexes was confirmed by carefully analyzing the rmsd and rmsf patterns retrieved from the MD trajectories. Several residues and areas (Leu124, Val123, Phe80, Leu83, Glu81, Arg 126, Asn132, Leu134, Gln131, Lys88 and Glu195) appear to be critical for inhibitor retention across the active pocket, according to RMSD and RMSF. The dynamics of the ligands inside the active pocket were mapped using principle component analysis. It has been observed that LIG1-3 appear to be the best possible inhibitors due to their high binding energies, interaction pattern and retention inside the active pocket. Communicated by Ramaswamy H. Sarma.