Identification of natural marine compounds as potential inhibitors of CDK2 using molecular docking and molecular
Basharat Ahmad1,2, Aamir Saeed2, Melvin A Castrosanto3
1National Institute for Genomics and Advanced Biotechnology (NIGAB), National Agricultural Research Centre (NARC), Islamabad, Pakistan.
Abstract:
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 (ΔGPB = -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.
Insights
This study identifies novel marine-derived compounds as potential inhibitors for cyclin-dependent kinase 2 (CDK2), a key protein in cell cycle regulation and cancer. These compounds show promising binding energies and stability, offering new therapeutic strategies for cancer treatment.
Area of Science:
- Biochemistry
- Pharmacology
- Computational Chemistry
Background:
- Cyclin-dependent kinase 2 (CDK2) is crucial for cell cycle progression and is implicated in diseases like cancer.
- Targeting CDK2 offers a promising therapeutic strategy in oncology.
Purpose of the Study:
- To identify novel inhibitors of the CDK2 ATP binding site using in silico drug design.
- To explore natural compounds from marine sources as potential CDK2 inhibitors.
Main Methods:
- Molecular docking was employed to screen marine-derived natural compounds against the CDK2 ATP binding site.
- Molecular dynamics (MD) simulations and MMPBSA calculations were used to evaluate binding energies and complex stability.
- Principal component analysis (PCA) was utilized to analyze ligand dynamics within the active pocket.
Main Results:
- Three compounds (LIG1, LIG2, LIG3) exhibited significant binding energies (ΔGPB = -19.98, -15.82, and -12.98 kcal/mol, respectively).
- MD simulations confirmed the stability of the ligand-protein complexes, with specific residues identified as critical for inhibitor binding.
- PCA revealed favorable dynamics and retention of the top compounds within the CDK2 active pocket.
Conclusions:
- LIG1, LIG2, and LIG3 are identified as potent potential inhibitors of CDK2 based on their binding affinity, interaction patterns, and stability.
- These marine-derived compounds represent promising candidates for further development as anti-cancer therapeutics targeting CDK2.
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