Synergistic Modulation Of Apoptotic Proteins By Curcumin And Chemotherapeutics: An Integrative Docking, Molecular Dynamics, And Free Energy Study

Abstract

Background: Apoptosis is central to breast cancer (BC) regulation, and its disruption promotes tumor progression and therapy resistance. Restoring apoptotic balance can enhance treatment outcomes.

Objective: To evaluate the anticancer potential of Curcumin (CUC), Docetaxel (DOC), and Carboplatin (CAP) against key apoptotic proteins in BC using integrative computational approaches.

Subjects and Methods: Apoptotic regulators including BAX, Caspase-9, Caspase-8, Caspase-3, BCL2, Wnt, and Integrin were analyzed using molecular docking, 200 ns molecular dynamics (MD) simulations, and MM-PBSA calculations to assess binding affinity, stability, and energetic contributions of single and combination drug interactions.

Results: CUC showed strong affinity for BAX and Caspase-9, while the CUC–DOC–CAP triple complex exhibited the greatest stability and lowest binding free energy among all systems. MD simulations confirmed enhanced compactness, sustained hydrogen bonding, and synergistic interactions, with MM-PBSA analysis indicating cooperative van der Waals and electrostatic contributions driving the superior stability of the triple-ligand complex.

Conclusion: CUC enhanced the chemotherapeutic performance of DOC and CAR by strengthening pro-apoptotic protein interactions, suggesting its promise as a chemosensitizer in BC therapy.