Identification of plant-derived secondary metabolites as potential CDK2 inhibitors against colorectal cancer: Molecular docking, dynamics simulations and DFT study

Colorectal cancer (CRC) ranks as the third most common cancer globally and remains the second leading cause of cancer-related deaths, with an estimated 1.9 million new cases and 0.93 million fatalities reported in 2020. While several synthetic drugs exist for CRC treatment, their adverse side effects necessitate the exploration of alternative therapies. This research identifies potential therapeutics from Piper betle secondary metabolites against CRC, leveraging their traditional uses and hypothesized lower toxicity. We targeted Cyclin-dependent Kinase 2 (CDK2), a key regulator of cell cycle progression implicated in CRC, for molecular docking to investigate the binding interactions of selected phytochemicals. Notably, Chlorogenic acid and Cianidanol exhibited significantly superior binding affinities (−8.7 kcal/mol) compared to the standard Capecitabine (−7.5 kcal/mol), indicating stronger interactions. 100 ns molecular dynamics (MD) simulations confirmed the stability and sustainability of these protein-ligand complexes through RMSD, RMSF, DCCM, PCA, and MM-PBSA analyses, providing insights into their molecular mechanisms. Drug-likeness and ADMET profiling revealed favorable pharmacokinetic properties and low toxicity for the identified compounds. Furthermore, PASS analysis suggested that these phytocompounds possess enhanced antioxidant and anticancer potential compared to Capecitabine. This study demonstrates that Chlorogenic acid and Cianidanol from Piper betle are promising leads for developing novel anti-colon cancer therapies.