Exploration of marine natural compounds as promising MDM2 inhibitors for treating triple-negative breast cancer: insights from molecular docking, ADME/T studies, molecular dynamics simulation and MM-PBSA binding free energy calculations

Triple-negative breast cancer (TNBC), the most aggressive form of breast cancer, presents a significant mortality risk owing to its elevated potential for metastasis. The overexpression of Murine Double Minute 2 homolog (MDM2) protein, a key suppressor of tumour suppressor p53, in TNBC amplifies its growth, advancement, and invasiveness. Thus, inhibiting MDM2 protein emerges as a compelling strategy to enhance the efficacy of TNBC treatment. We aimed to identify novel potential MDM2 inhibitors from natural marine compounds, known for their distinctive chemical structures and heightened anticancer activities, utilizing molecular docking, ADME/T analysis, molecular dynamics (MD) simulations, MM-PBSA calculations, and in silico PASS predictions. A marine compound library was constructed for initial screening purpose and the molecular docking analysis revealed that two marine compounds, namely 10,11-dihydrosodwanone B and sodwanone T, exhibited significantly higher binding affinity (− 9.6 kcal/mol and − 9.1 kcal/mol, respectively) compared to the established inhibitor nutlin-3a (− 8.4 kcal/mol). ADME/T investigations were conducted to ensure the drug-likeness properties and safety of these compounds. Additionally, in silico PASS tool predicted that both compounds possess a heightened potential for anticancer activities. Molecular dynamics simulations (100 ns) and MM-PBSA calculations indicated that sodwanone T formed a relatively more stable complex and had a higher binding-free energy with MDM2, respectively. In conclusion, this research suggests sodwanone T as a promising candidate for further testing and development as an MDM2 inhibitor for potential therapeutic applications against TNBC. Nevertheless, substantial experimental and clinical investigations are necessary to enhance its applicability in clinical settings.