Isolupalbigenin as a multi-target natural scaffold targeting HER2, EGFR, IGF-1R, and BCL-2 in breast cancer: An integrated docking, molecular dynamics, and DFT study

This study aimed to identify potential multi-target natural compounds capable of interacting with key breast cancer–associated proteins using an integrated computational framework. A curated library of twenty prenylated isoflavones was evaluated through molecular docking, ADMET profiling, molecular dynamics simulations, binding free-energy calculations, and density functional theory (DFT) analysis. Docking was performed against HER2, EGFR, IGF-1R, and BCL-2. Isolupalbigenin emerged as the most promising compound, exhibiting favorable drug-likeness and predicted safety profiles. Docking analyses revealed stable binding orientations within catalytic pockets supported by hydrogen bonding and hydrophobic interactions. Molecular dynamics simulations demonstrated sustained ligand confinement, stable backbone deviations, and restricted conformational sampling. Binding free-energy calculations indicated energetically favorable interactions predominantly driven by van der Waals contributions, while DFT analysis suggested moderate electronic stability and balanced donor–acceptor characteristics. Isolupalbigenin demonstrates computationally predicted structural compatibility across multiple breast cancer–associated targets and may serve as a promising natural scaffold for further investigation. However, these findings are derived exclusively from computational analyses and require experimental validation.