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<p>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 (ΔG<sub>bind</sub> ≤ −70&#xa0;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&#xa0;kcal/mol; post-DFT ΔG<sub>bind</sub>: −79.64&#xa0;kcal/mol), forming sixteen stabilising interactions within the COX-2 active site. Molecular dynamics simulations (350&#xa0;ns, AMBER20) confirmed the complex's stability (RMSD: 2.27–2.83&#xa0;Å; RMSF &lt; 1&#xa0;Å), structural compactness (RoG &lt; 24.00&#xa0;Å), and reduced solvent exposure. Post-simulation MM/GBSA analysis reaffirmed strong binding (ΔG<sub>bind</sub>: −74.21&#xa0;kcal/mol), driven by van der Waals and electrostatic forces. Subsequently, Frontier molecular orbital (FMO) analysis further demonstrated high electronic reactivity (ΔE: 5.50&#xa0;eV; softness: 0.36&#xa0;eV⁻<sup>1</sup>), 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.</p> Graphical Abstract <p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月5日

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  • Vitalis Mbayo,
  • Vincent A. Obakachi,
  • Penny P. Govender,
  • Krishna K. Govender

摘要

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.

Graphical Abstract