Targeting Nudix Hydrolase 5 with Bioactive Flavonoids: Molecular Dynamics and Docking Studies for Breast Cancer Therapy

Breast cancer (BC) is the most prevalent malignancy among women globally and the leading cause of cancer-related mortality. Consequently, there is an urgent need for new, effective treatment strategies for breast cancer. Research has shown that the enzyme nudix hydrolase 5 (NUDT5) plays a critical role in promoting breast cancer aggressiveness and serves as a key regulator of oncogenic pathways. The development of NUDT5 inhibitors presents a viable strategy for enhancing treatment results in managing BC. The ability of the flavonoids to modulate key biochemical pathways and improve therapeutic outcomes highlights their promise in developing novel breast cancer treatments. Hence, the main objective of the present investigation is to identify the potential interaction of structurally diverse bioactive flavonoids with the active site of the target NUDT5. Our docking analysis revealed that the flavonoids such as naringin and genistein have shown a significant binding association with residues Arg51, Asp60, Gln82, Arg84, Ala96, Leu98, Glu112, Glu116, Met132, Cys139, Ile141, and Glu166 of NUDT5, suggesting its potential as a potent inhibitor. The stabilizing effects of these leads (naringin and genistein) were further validated using molecular dynamics investigations, including RMSD, RMRF, Rg, SASA, PCA, and FEL. The results of the MD simulation studies evidenced a more significant interaction between genistein and NUDT5, indicating a steady and robust affinity, making genistein a more promising inhibitor. In conclusion, the flavonoid genistein has a strong potential as a therapeutic agent for targeting NUDT5 in breast cancer treatment making it viable candidates for further preclinical and clinical investigations.