Unraveling the Anti-Atherosclerotic Potential of Bee Pollen: A Synergistic Approach Combining Gene Expression Profiling, Molecular Docking, DFT, and Dynamics

• The anti-atherosclerotic potential of bee pollen was systematically investigated using integrated computational approaches. • Gene expression profiling and network analysis identified core atherosclerosis-related targets modulated by bee pollen constituents. • Molecular docking and molecular dynamics simulations confirmed strong and stable binding affinities between bee pollen compounds and key therapeutic targets. • Density Functional Theory (DFT) analysis revealed lead bee pollen compounds with favourable reactivity and stability for future drug development. • The study underscores bee pollen's promise as a natural multi-targeted agent for atherosclerosis intervention. Bee pollen is a natural product that has been used to treat atherosclerosis for thousands of years. This study aims to investigate the anti-atherosclerotic potential of the bioactive metabolites of bee pollen utilizing network pharmacology, system biology, and other methods. A total of 30 bioactive compounds from previously published data were compiled and analyzed further. Gene ontology (GO) and KEGG pathway enrichment analysis were performed by using the Database for Annotation, Visualization, and Integrated Discovery (DAVID). **Network pharmacology and GSE23746 gene expression analysis identified BCL2, STAT3, PPARG, CASP3, MMP9, and CXCL8 as central atherosclerosis-related protein targets involved in inflammation, lipid metabolism, and apoptosis. The four lead polyphenols—epicatechin, catechin, resveratrol, and apigenin—exhibited favorable electronic properties and docking profiles with moderate binding affinities (-5 to -7kcal/mol), consistent with multi-target effects typical of polyphenols. The protein-ligand complexes simulated showed moderate conformational stability, as measured by RMSD, RMSF, secondary structure formation, hydrogen bonding, and the ligand dynamics. The 3-dimensional Free Energy Landscape (FEL) based on Principal Component Analysis (PCA) projections was used to elucidate the predominant conformational movements and structural characteristics of the four proteins. Epicatechin exhibited the highest chemical reactivity based on its narrow energy gap and low ionization energy (DFT descriptors). These findings indicate the therapeutic potential of a multi-targeted natural agent for atherogenesis management, warranting experimental validation, offering a scientific foundation for its further development.