Computational Predicted Mechanism of Tiliroside Compound Against Triple-Negative Breast Cancer Using Network Pharmacology and Induced-Fit Docking Approach

Abstract

BACKGROUND: Triple-negative breast cancer (TNBC) progression is driven by dysregulation of multiple interconnected signaling pathways rather than a single molecular abnormality, but current treatment strategies TNBC primarily rely on single-target therapy, highlighting the need for therapeutic candidates that may target multiple signaling pathway of TBNC. Tiliroside, a naturally occurring flavonoid glycoside, has demonstrated promising anticancer activity; however, its predicted effects on TNBC-associated oncogenic signaling networks remain poorly understood. Therefore, this study aimed to investigate the predicted molecular mechanisms by which tiliroside may modulate TNBC-associated oncogenic signaling networks.

METHODS: Integrated computational approach combining network pharmacology, comparative molecular docking, and induced-fit docking was employed. Potential targets of tiliroside were predicted using SwissTargetPrediction and intersected with TNBC-associated genes retrieved from GeneCards. Protein–protein interaction and KEGG pathway enrichment analyses were performed to identify key molecular targets and signaling pathways. Comparative molecular docking was subsequently conducted using 19 structurally related flavonoids with reported anticancer activities against the identified hub proteins, followed by induced-fit docking to characterize the binding mechanism of tiliroside.

RESULTS: Fifteen overlapping targets were identified between tiliroside and TNBC. Network analysis highlighted Akt serine/threonine kinase 1 (AKT1), sarcoma (SRC), and epidermal growth factor receptor (EGFR) as the principal hub genes, while the KEGG enrichment revealed significant involvement of phosphoinositide 3-kinase (PI3K)–AKT, erythroblastic leukemia viral oncogene B (ErbB), EGFR tyrosine kinase inhibitor resistance, focal adhesion, and vascular endothelial growth factor (VEGF) signaling pathways. Tiliroside consistently exhibited one of the most favorable binding profiles among the evaluated flavonoids, with binding energies of −9.41, −8.62, and −8.25 kcal/mol toward AKT1, SRC, and EGFR, respectively. Induced-fit docking further confirmed stable hydrogen-bond and hydrophobic interactions within the active sites of these proteins.

CONCLUSION: Tiliroside exerts potential anti-TNBC activity through multitarget modulation of interconnected oncogenic signaling pathways, suggesting that tiliroside might be a promising lead compound for TNBC.

KEYWORDS: tiliroside, triple-negative breast cancer, network pharmacology, induced-fit docking