Binding Interaction and Stability Analysis of Quercetin and its Derivatives as Potential Inhibitors of Triple Negative Breast Cancer (TNBC) against PARP1 Protein: An in-silico Study.

Background: Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by the absence of estrogen and progesterone receptors (ER, PR) and low or absent HER2 expression, limiting treatment options. Quercetin, a flavonoid with anti-cancer properties, has the potential to be a therapeutic intervention.

Objectives: The study aimed to explore the potential of Quercetin derivatives as therapeutic agents for TNBC using several computational methods.

Methods: The study utilized PASS prediction, molecular docking, ADMET prediction, QSAR models, MD simulations, binding free energy, and DFT calculations to evaluate the efficacy of quercetin derivatives.

Results: ADMET analysis confirmed the solubility, non-carcinogenicity, and low toxicity of four quercetin derivatives: LM01, LM02, LM05, and LM10. These derivatives exhibited strong binding affinity against TNBC protein PPAR1, with binding energies of -10.6, -10.7, -11.4, and -10 kcal/mol, respectively. MD simulations confirmed their stability, with consistent RMSD values and favorable RMSF values. Post-simulation calculations and reduced HOMO-LUMO energy gaps further supported their potential as promising candidates.

Conclusion: Our computational findings suggest that quercetin derivatives, particularly LM01, LM02, and LM10, exhibit strong stability and binding affinity, positioning them as promising candidates for TNBC treatment. Further experimental validation is required to confirm their therapeutic potential.