DFT and molecular docking studies of <i>p</i> -nitrobenzyl-derived Brevilin A as a potential anticancer agent

Abstract The electronic structure and anticancer potential of p -nitrobenzyl-modified Brevilin A (BA-9) were systematically investigated using density functional theory (DFT) and molecular docking approaches. The structural modification and its impact on electronic properties represent a key novelty of this study. The optimized geometry of BA-9 exhibited strong agreement with expected bond lengths and angles, confirming structural stability. Frontier molecular orbital and natural population analyses revealed distinct nucleophilic and electrophilic regions, with the nitro group acting as a strong electron-withdrawing substituent that modulates charge distribution. The calculated HOMO–LUMO energy gap suggests moderate chemical reactivity and enhanced molecular stability. Time-dependent DFT (TD-DFT) simulations produced UV–Vis absorption bands consistent with experimental observations, while B3LYP/6-31G(d,p)-calculated 1 H and 13 C NMR chemical shifts closely matched reported data, validating the proposed structure. In addition, drug-likeness evaluation and ADME/Tox predictions indicate that BA-9 satisfies Lipinski’s rule of five, supporting its favorable pharmacokinetic profile. Molecular docking studies against key cancer-related targets, including ALK kinase, KRAS-G12D, ERRγ, and ERα, demonstrated strong binding affinities mediated by hydrogen bonding, π – π stacking, and hydrophobic interactions. Overall, this study provides mechanistic insights into how p -nitrobenzyl modification enhances the electronic characteristics and target-binding potential of Brevilin A, highlighting BA-9 as a promising lead compound for anticancer drug development.