Exploring Natural Compound Libraries for Breast Cancer Targets: An <i>In Silico</i> Study

Background: Breast cancer is a globally prevalent, heterogenous disease affecting both women and men across all ethnic groups. It is a complex disease and is the second most frequently diagnosed solid tumour in women worldwide. The PI3K/AKT/mTOR signalling pathway plays a significant role in breast cancer progression, survival, and drug resistance. It is dysregulated in approximately 20-34% of cases, making it a key target for therapeutic intervention. Aim: This study aims to investigate the potential of natural compounds against the PI3K/AKT/mTOR signalling pathway using molecular docking studies to evaluate their binding affinity and interactions with target proteins. Methods: Molecular docking was performed to analyse the binding energy, conformational changes, and amino acid interactions of selected natural compounds with PI3K and AKT. Results: Our virtual molecular docking studies suggest that the natural compounds ginsenoside (-7.39 kcal/mol), nimbolide (-6.22 kcal/mol), and pristimerin (-6.28 kcal/mol) exhibit strong binding affinities toward PI3K, indicating their potential as pathway inhibitors. Additionally, pristimerin (-5.52 kcal/mol), curcumin (-5.63 kcal/mol), and ginsenoside (-6.07 kcal/mol) demonstrated strong interactions with AKT. Conclusion: The docking results suggest these natural compounds exhibit strong interactions with PI3K and AKT, indicating their potential as effective pathway inhibitors. The favourable binding affinities suggest that these compounds may serve as promising candidates for targeted breast cancer therapy, especially for patients with PI3K/Akt pathway dysregulation. Further experimental validation is required to confirm their therapeutic efficacy. Major Findings: Nimbolide, pristimerin, and ginsenoside demonstrate significant therapeutic potential in breast cancer treatment by modulating the PI3K/AKT signalling pathway.