Multi-target drug discovery of Sclerocarya birrea bioactive moieties against drug resistance in triple-negative breast cancer (TNBC) targeting BCL2, CASP3, and JUN modulation; a polypharmacological and molecular modelling approach

Abstract

Abstract Triple-negative breast cancer (TNBC) remains one of the most aggressive breast cancer subtypes, characterized by poor prognosis and limited therapeutic options due to drug resistance. In this study, a network pharmacology-based multi-target drug discovery approach was applied to explore the therapeutic potential of Sclerocarya birrea bioactive moieties against TNBC. Initially, hub genes implicated in TNBC progression and drug resistance, including TP53, BCL2, IL6, CASP3, and JUN, were identified through protein–protein interaction and pathway enrichment analyses. Molecular docking revealed that several bioactive compounds from S. birrea , particularly Pseudolaric Acid derivatives, demonstrated high binding affinities across multiple targets, often exceeding those of the reference controls. Hierarchical clustering and correlation analysis further highlighted structural and functional similarities among the compounds, suggesting a consistent multi-target binding profile. Molecular dynamics simulations confirmed the stability of key hub gene–compound complexes, with reduced RMSD, RMSF, and favorable solvent-accessible surface area (SASA) compared with controls, indicating enhanced conformational stability upon ligand binding. Per-residue energy decomposition pinpointed critical residues contributing to binding, while thermodynamic profiling showed that the binding was primarily driven by van der Waals and electrostatic interactions, with Pseudolaric Acid H (BCL2), DMHCA (CASP3), and Pseudolaric Acid B (JUN) achieving significantly more favorable free energies than controls. These findings suggest that S. birrea bioactive compounds exert their therapeutic effect through a synergistic, multi-target mechanism, enhancing apoptotic regulation while overcoming resistance-associated pathways. This integrative in silico study provides a mechanistic blueprint for repurposing S. birrea phytoconstituents as potential multi-target therapeutics for TNBC. Pseudolaric Acid H, DMHCA, and Pseudolaric Acid B were identified as promising compounds that exhibited favorable interactions with key proteins associated with TNBC drug resistance. These findings suggest their potential to modulate drug resistance-related pathways and warrant further experimental validation. The results not only highlight their capacity to reverse drug resistance but also underscore their promise as scaffolds for further development in anti-TNBC drug discovery.