Carbazole alkaloids Koenigicine, Koenigine, Mahanine and Mukonicineas Multi-Target Inhibitors in Triple-Negative Breast Cancer: Insights into MMP9, MMP13, EGFR, and NUDT5 Interactions through Molecular Docking

Plant-based natural products have been widely used for treating and preventing diseases due to their nutritional and pharmacological benefits, significantly improving the health and well-being of individuals. These medicinal plants are also easily accessible and offer a low-cost, less harmful source for developing new medications. Breast cancer is the second most common form of cancer reported in women worldwide. The treatment of triple-negative breast cancer (TNBC) remains challenging, as this subtype lacks targeted therapeutics. TNBC accounts for approximately 15-20% of newly diagnosed breast cancer cases. Because TNBC tumors do not express estrogen receptors (ER), progesterone receptors (PR), or human epidermal growth factor receptor 2 (HER2), patients with TNBC do not benefit significantly from treatments aimed at ER, PR and HER2-positive breast tumors. While TNBC initially responds well to chemotherapy, it often develops resistance over time, complicating disease management and presenting a significant clinical challenge. To address therapy resistance and improve patient outcomes, exploring new therapeutic options for TNBC is essential. This molecular docking study shows strong interactions between the carbazole alkaloids Koenigicine, Koenigine, Mahanine, and Mukonicine with key oncogenic protein targets such as MMP9, MMP13, NUDT5, and EGFR, which are associated with TNBC progression. The binding energy of these molecules ranges from -7.4 to -9.9 kcal/mol, indicating a very high potential for inhibition. Mahanine exhibits the highest binding affinity for all tested targets, demonstrating strong interactions with NUDT5 (-9.8 kcal/mol) and EGFR (-9.9 kcal/mol). This suggests its potential role as a multi-target inhibitor. The primary non-covalent interactions that contribute to the binding of carbazole alkaloids with target proteins include Van der Waals forces, hydrogen bonds, alkyl interactions, π-alkyl interactions, and π-π stacking. These interactions are crucial for stabilizing the ligand-protein complexes, enhancing binding affinity, and likely influencing the inhibitory effects of the compounds on TNBC-associated oncogenic proteins. The results of this study highlight the potential role of carbazole alkaloids in TNBC treatment, warranting further experimental validation.