Molecular-level insights into the antitumor activity of ellipticine derivatives targeting CDK2 in hepatocellular carcinoma: An advanced computational study.

Ellipticine-derived compounds (OBr-, OCl-, OF-, and NHCl-substituted analogues) were comprehensively investigated in silico as potential cyclin-dependent kinase 2 (CDK2) inhibitors relevant to hepatocellular carcinoma. An integrated multi-scale computational workflow combining density functional theory (DFT), ADMET prediction, molecular docking, and molecular dynamics (MD) simulations was employed to provide a robust and holistic validation strategy for candidate prioritization and to enhance prediction reliability. DFT calculations revealed favorable electronic descriptors, including well-distributed frontier molecular orbitals and reactive electrostatic potential regions indicative of strong protein-binding propensity. Pharmacokinetic profiling predicted high intestinal absorption, low toxicity risk, and absence of blood-brain barrier permeation, supporting desirable drug-like characteristics. Molecular docking analyses demonstrated stronger binding affinities of all derivatives compared with the reference inhibitor 2-aminopurine, along with consistent and stable interaction patterns within the CDK2 active site. Subsequent MD simulations confirmed the structural stability of ligand-protein complexes and the persistence of key intermolecular interactions throughout the simulation time, reinforcing the reliability of docking predictions. Overall, the combined multi-level computational approach highlights ellipticine analogues as promising CDK2-targeting candidates with favorable electronic, pharmacokinetic, and binding properties. This integrative strategy underscores their potential as rationally designed therapeutic leads and supports their further investigation for hepatocellular carcinoma treatment.