<i>Abelmoschus sagittifolius</i> phytochemicals as potential CDK2 inhibitors for cancer therapy: Insights from ADMET, DFT, and ONIOM studies

Abstract This study employs advanced computational techniques to explore the potential of 19 phytochemicals isolated from Abelmoschus sagittifolius as inhibitors of CDK2. A multi‐scale computational framework was utilized, integrating drug‐likeness evaluation, pharmacokinetic analysis, density functional theory (DFT), and ONIOM simulations, to deliver an in‐depth evaluation of the anticancer potential of these compounds. Among the nineteen analyzed compounds, twelve exhibited favorable pharmacokinetic profiles, as determined by drug‐likeness and ADMET analyses. Electronic structure calculations, including parameters like electron affinity, ionization energy and electrophilicity, provided critical insights into the chemical reactivity and stability of the studied phytochemicals. Electrostatic potential (ESP) surface mapping further elucidated the roles of functional groups in modulating molecular reactivity and interaction potential, with particular emphasis on electrophilic and nucleophilic sites. The ONIOM approach (M06‐2X/6‐31+G(d):PM6:UFF) revealed substantial inhibitory activity of the compounds against CDK2. Notably, compound 12 (marmesinin) exhibited the highest binding affinity (−50.6 kcal/mol), surpassing the reference drug, 5‐fluorouracil (−17.2 kcal/mol). Key residues within the CDK2 active site, including Lys33, Asp86, and Lys89, were identified as critical for ligand binding, mediating interactions through CH···π, H···H, and hydrogen bonding. These results highlight the essential role of noncovalent interactions (NIC) in developing selective and effective CDK2 inhibitors. This study not only highlights the anticancer potential of Abelmoschus sagittifolius ‐derived phytochemicals but also provides a robust computational framework for the strategic development of targeted anticancer therapeutics with enhanced effectiveness and precision.