Abstract
Objective: The research objective is to explore the potential for synergistic inhibition of two curcumin analogs combined with 5-fluorouracil (5-FU) against the B-cell lymphoma 2 (BCL-2) protein.
 Methods: We investigated the synergistic inhibition of two curcumin analogs, namely, (1E,4E)-1,5-bis(4-hydroxyphenyl)penta-1,4-dien-3-one (AC01) and (1E,4E)-1,5-bis(3,4-dihydroxyphenyl)penta-1,4-dien-3-one (AC02), each combined with 5-FU by calculating their binding free energies and binding stability. An in silico investigation of the synergistic interaction of ligand pairs was conducted using the multiple ligand simultaneous docking (MLSD) technique with the AutoDock Vina package. The stability of interactions and binding free energies of each BCL-2 and curcumin analogs were examined by applying molecular dynamics techniques with the Gromacs package and MMPBSA method.
 Results: All ligand pairs had displayed strong binding affinity, as evidenced by highly negative free energy values, indicating a robust association with BCL-2. Molecular dynamics simulations were conducted over 100 ns, confirming good stability with controlled RMSD changes, suggesting that the ligand pairs had remained securely bound to the BCL-2 binding site. Additionally, RMSF analysis and energy decomposition had revealed that ligand interactions did not influence protein residue fluctuations during the simulation, and the protein-ligand complexes had maintained stability throughout the simulation. Furthermore, binding free energy calculations using the MMPBSA method had consistently shown negative values, signifying stable interactions with BCL-2 for all ligand pairs.
 Conclusion: In conclusion, our study revealed that AC01 and AC02, when combined with 5-FU, had the ability to intercalate into the P2 and P4 sites of BCL-2. This suggested that AC01 and AC02 held promise for further study as candidates for anticancer drugs, individually or in combination with 5-FU.
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