Introduction: Despite therapeutic advancements, breast cancer remains a formidable clinical challenge, necessitating innovative therapeutic strategies that combine high specificity with enhanced potency. To address this need, we rationally engineered a novel fusion protein that integrates the membrane-lytic activity of magainin-2 with the tumor-targeting capability of interleukin-24 (IL-24), aiming to significantly enhance selective cytotoxicity against breast cancer cells. Methods: A 3D model of the magainin 2–IL-24 fusion protein was generated using AlphaFold2 and subsequently subjected to rigorous refinement, structural validation, and comprehensive assessment of its physicochemical properties. Results: Structural validation via Ramachandran plot and ERRAT2 analyses confirmed the robust structural quality of the model. Molecular docking studies revealed 11 hydrogen bonds and additional intermolecular contacts, including salt bridges, between the fusion protein and its cognate receptor, indicating strong and highly specific interactions. Molecular dynamics simulations conducted over 100 ns further validated the conformational stability of the docked complex. Conclusion: These findings highlight the fusion protein’s capacity to combine targeted delivery with membrane disruption, offering a potent dual-action mechanism. This study provides a robust scientific rationale and computational evidence that the successful in vitro expression of the magainin 2–IL-24 fusion gene could yield a promising next-generation therapeutic candidate for breast cancer treatment.
Rehman et al. (Thu,) studied this question.