Naringenin and its structural analogues inhibit CDK2: a combined MD-MMGBSA and protein-ligand interaction study for colon cancer.

Cyclin-dependent kinase 2 (CDK2) is an important regulatory factor of the G1-S phase transition of the cell cycle, and a promising target for developing therapies to treat colon cancer. In this study, Naringenin and versions of its structure (Poriol, 7-Hydroxyflavanone, and Farrerol) were evaluated for their inhibitory potential using a multi-level in silico approach involving molecular docking, density functional theory (DFT), molecular dynamics (MD) simulation, and MMGBSA binding free energy. Naringenin bound with the most favourable affinity (ΔG_bind = - 43.55 kcal/mol) to CDK2, which stabilized binding through important active site residue contacts (LEU83, ILE10, and VAL18). DFT derived reactivity descriptors and electrostatic potential maps identified the carbonyl group as a key site of protein-ligand recognition. After 200 ns of MD simulation, Naringenin had a stable structure (i.e., RMSD values), and MMGBSA and residue decomposition analyses of each molecule supported favourable binding space energetically. Overall, our study indicated that Naringenin may be a lead compound in drug development targeting CDK2. However, the anticancer potential and pharmacokinetic properties need to be validated with in vitro and in vivo studies. This study demonstrates a rational basis to move Naringenin-based scaffolds forward in preclinical cancer research by employing computational and translational pharmacology. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-025-00420-7.