Chemoinformatics profiling of Annona muricata-derived compounds targeting COX-2 in breast cancer

Breast cancer remains one of the leading causes of cancer-related mortality globally, with a disproportionate impact in low- and middle-income countries, with cyclooxygenase-2 (COX-2) overexpression promoting tumour progression, angiogenesis, and therapy resistance. This Insilico study explored the chemical diversity of Annona muricata (soursop) to identify potent COX-2 inhibitors using an integrated in silico workflow. A library of 52,242 natural compounds was screened through high-throughput virtual screening and Glide extra-precision (XP) docking against COX-2 (PDB ID: 3LN1). From 104 preliminary hits, 27 leads were prioritised via Prime MM/GBSA (ΔGbind ≤ −70 kcal/mol), and DFT optimisation (M06-2X/def2-SVP) highlighted five top candidates: Tellimoside, Hamamelitannin, Catechin-4-ol 3-O-α-L-rhamnopyranoside, Avicularin, and Myricetin-3-O-arabinofuranoside. Tellimoside exhibited the highest affinity (Glide score: −13.58 kcal/mol; post-DFT ΔGbind: −79.64 kcal/mol), forming sixteen stabilising interactions within the COX-2 active site. Molecular dynamics simulations (350 ns, AMBER20) confirmed the complex's stability (RMSD: 2.27–2.83 Å; RMSF < 1 Å), structural compactness (RoG < 24.00 Å), and reduced solvent exposure. Post-simulation MM/GBSA analysis reaffirmed strong binding (ΔGbind: −74.21 kcal/mol), driven by van der Waals and electrostatic forces. Subsequently, Frontier molecular orbital (FMO) analysis further demonstrated high electronic reactivity (ΔE: 5.50 eV; softness: 0.36 eV⁻1), indicating favorable adaptability within the active site. These results suggest that A. muricata-derived polyphenols, particularly Tellimoside, are computationally predicted scaffolds for selective COX-2 inhibition and may serve as adjuvant therapeutics that may guide future experimental validations for breast cancer management.