Identification of potential breast cancer therapeutics from non-phenolic diarylheptanoids of Curcuma xanthorrhiza using network pharmacology and in silico methods

Abstract Background Curcuma xanthorrhiza , a widely recognized medicinal plant, contains three non-phenolic diarylheptanoids (NPDs) that exhibit diverse biological properties. Despite their known bioactivities, the precise molecular mechanisms underlying their therapeutic potential, particularly in breast cancer (BRCA) treatment, remain largely unexplored. This study aims to elucidate the potential mechanisms by which NPDs may act against BRCA, employing a combination of network pharmacology, molecular docking, molecular dynamics (MD) simulations, and molecular mechanics/generalized Born surface area (MM/GBSA) analysis. Method BRCA- and NPD-associated targets were retrieved from multiple databases to construct a protein–protein interaction (PPI) network. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) platform to identify relevant biological processes and signaling pathways. Molecular docking was used to predict the binding affinities between NPDs and key protein targets, which were further validated through MD simulations and MM/GBSA calculations. Results From 436 BRCA-related and 266 NPD-associated targets, 24 core targets were identified. Thirteen hub targets, including Erythroblastic oncogene B and B 2 (ERBB2), Epidermal Growth Factor Receptor (EGFR), Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha (PIK3CA), and Mouse Double Minute 2 (MDM2), were found to be enriched in the KEGG cancer pathway (hsa05200). Among these, ERBB2 emerged as a top candidate for further analysis. Furthermore, the molecular docking results revealed that the NPD exhibited a comparable binding affinity toward the ERBB2 protein, with docking scores ranging from − 8.2 to − 8.5 kcal/mol, whereas the control compound, neratinib, demonstrated a slightly stronger binding affinity of − 9.6 kcal/mol. The MD simulations further confirmed the stability of the interactions, as compounds 2 and 3 maintained stable protein–ligand complexes with consistent root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), and solvent-accessible surface area (SASA) profiles throughout the simulation. Moreover, the binding free energy calculations reinforced these findings, showing strong interactions between ERBB2 and compounds 2 and 3, with values of − 29.76 and − 25.27 kcal/mol, respectively. Conclusion The integrated computational approach suggests that NPDs have the potential to act as ERBB2 inhibitors, offering promising prospects for BRCA therapy.