Electronic Structure and Topology‐Based Insights into Andrographolides as Potential CDK2 Inhibitors: Comprehensive DFT and Molecular Dynamics Investigation

ABSTRACT Andrographolide is a bicyclic diterpenoid lactone that has garnered considerable interest for its potential therapeutic applications, particularly in anticancer effects. Cyclin‐dependent kinases (CDKs), especially CDK2 and its regulatory subunits, are dysregulated in many human cancers, and emerging evidence suggests that CDK2 inhibition induces antitumor activity. This study provides a comprehensive analysis of the electronic structure and topology of three distinct andrographolide derivatives (AG‐OH, AG‐NO 2 , and AG‐Cl) to assess their efficacy as inhibitors of CDK2. Density functional theory (DFT) calculations are utilized to examine frontier molecular orbitals (FMOs), electrostatic potential (ESP) surfaces, and natural bond orbital (NBO) interactions, yielding detailed insights into their reactivity, electronic distributions, and intramolecular charge transfer properties. The reduced density gradient (RDG) and non‐covalent interaction analyses elucidated critical stabilization regions and interaction intensities among the derivatives. ADMET calculations demonstrated that all derivatives adhered to Lipinski's rule of five and exhibited advantageous pharmacokinetic characteristics, including moderate lipophilicity (Consensus LogP 2.58–4.06) and acceptable polarity (TPSA 86.99–132.81 Å 2 ), indicating their potential as CDK2 inhibitors. Molecular docking studies demonstrated robust binding affinities in the range −9.2–−10.2 kcal/mol, later validated by molecular dynamics (MD) simulations, where the RMSD remained stable approximately at 0.2 nm. Calculations of binding free energy using MM‐GBSA confirmed the strong and stable nature of the complex, with binding energy values ranging from −26.54 to −39.70 kcal/mol, exhibiting significantly favorable energetics. Our thorough computational analysis identifies andrographolides as potential CDK2 inhibitors, providing valuable insights for future experimental validation and potential development as anticancer agents.