Integrated network pharmacology and molecular docking analysis of Hedychium spicatum phytochemicals as potential ESR1 inhibitors for pancreatic cancer therapy

Pancreatic cancer, particularly pancreatic ductal adenocarcinoma (PDAC), remains one of the most aggressive malignancies with poor prognosis and limited therapeutic options. The present study employed an integrated network pharmacology and molecular docking approach to explore the anticancer potential of phytochemicals derived from Hedychium spicatum against PDAC, with a focus on estrogen receptor alpha (ESR1) as a potential therapeutic target. Sixty phytochemicals were retrieved from natural product databases, and 40 compounds met the drug-likeness criteria for further analysis. Target prediction using the Similarity Ensemble Approach identified 439 potential protein targets, and intersection analysis with pancreatic cancer-related genes revealed 10 common targets. Protein–protein interaction network analysis identified five most connected nodes within this intersection set: ESR1, HDAC1, PPARG, TERT, and CASP3. Gene Ontology and KEGG pathway enrichment analyses revealed that these targets are primarily involved in transcriptional regulation, apoptosis, and cancer-related signaling pathways. ESR1 was selected for molecular docking due to its network centrality and druggability. Docking studies demonstrated that four phytochemicals, hedychia lactone B, spicatanol, spicatanol methyl ether, and chrysin, exhibited strong binding affinities toward ESR1, surpassing or comparable to reference compounds tamoxifen and TS7. These interactions were further validated in both wild-type and R269C mutant ESR1 models. Toxicity assessment using ProTox-3.0 indicated favorable safety profiles, particularly for chrysin and hedychia lactone B, while ADMET analysis suggested high gastrointestinal absorption, good solubility, and acceptable pharmacokinetic properties. Overall, this study provides a systematic computational framework identifying promising H. spicatum phytochemicals as potential ESR1-targeted agents in pancreatic cancer. However, these findings remain exploratory and require experimental validation to confirm their therapeutic efficacy.