Network pharmacology and computational dissection of Solanum trilobatum bioactives reveals modulation of steroid receptor associated signalling in breast cancer

Abstract Background Breast cancer is the most common form of malignancy in women worldwide. Although chemotherapy has been improved, the major drawbacks demand alternative treatment plans. Bioactives based on plants have become a key focus of interest as complementary agents and Solanum trilobatum has been known to possess multiple pharmacological activities that include, antioxidant, antimicrobial, anti-inflammatory, and anti-cancer effects. The molecular paths of action of its anticancer effect, however, is mostly unexplored. Methods An integrative in silico strategy combining network pharmacology, molecular docking, molecular dynamics (MD) simulations, and binding free energy calculations was employed to elucidate the anticancer mechanisms of S. trilobatum bioactives. Phytoconstituents were mined from curated databases and screened based on drug-likeness, ADMET properties, and predicted anti-neoplastic activity. Protein protein interaction networks, KEGG pathway enrichment, and Gene Ontology analyses were performed to identify key pathways and hub genes. Selected bioactives were docked against oncogenic targets using AutoDock Vina and Schrödinger Glide. The most promising protein ligand complexes were further validated through long-timescale MD simulations and MMPBSA binding free energy analysis. Results The enrichment of the analysis by KEGG pathways demonstrated the PI3K-Akt signalling pathway as the pathway that was massively altered. Network analysis identified AKT1, TP53, TNF, STAT3, MYC, IL6, HIF1A, EGFR, CTNNB1, and CASP3 as hub genes. Molecular docking of rheochrysin, hypoxiside, cytochalasin and 4- p- coumatoylquinic acid to oncogenic proteins, HRAS, KRAS, NCOA3 (a nuclear coactivator of steroid receptors), PGR, and PIK3CB oncogenes was observed using AutoDock 4.2 and Schrodinger Glide with binding affinities displaying strong binding. Molecular dynamics simulations further confirmed stable and sustained interactions, particularly between KRAS–4-p-coumaroylquinic acid and TP53–Hypoxoside A complexes. Conclusion These findings provide mechanistic insights into the anticancer potential of S. trilobatum , supporting its role as a promising source of bioactive compounds capable of modulating steroid receptor–associated signalling networks in breast cancer therapy. Graphic abstract