Engineering of the Melanoma Inhibitor of Apoptosis (ML‐IAP) Anticancer Peptide Through Comprehensive In Silico Approaches

Background and Aims Melanoma represents the most malignant type of skin cancer. It is estimated that approximately 100,000 new cases of melanoma were diagnosed in 2022, resulting in over 7600 deaths in the United States alone. Recently, anticancer peptides (ACPs) have emerged as novel therapeutic agents for cancer, offering higher potency, biocompatibility, and fewer adverse reactions in host cells. One of the druggable targets of melanoma is the melanoma inhibitor of apoptosis (ML‐IAP), conventionally inhibited by the nonapeptide AVPIAQKSE. The current study is aimed at enhancing both the binding affinity and safety profile of this peptide through in silico peptide engineering. Methods Initially, the 3D structure of the protein was downloaded from the Protein Data Bank (PDB) (ID: 1OXQ) and prepared. The hotspot residues at the interface were detected using Discovery Studio Client 2021. Afterwards, saturation mutagenesis was conducted to discover the best potential amino acid substitutions with a positive impact on the binding affinity. The lead candidates were docked to the receptor via HPEPDOCK 2. Additionally, the safety profile was assessed using the ToxIBTL and AllerCatPro 2 servers. Finally, molecular dynamics simulations and principal component analysis were performed to check the stability of the best complexes. Results HVPIAQKSE, WVPWAQKSE, and HVPWAQKSE were the best mutants that could be superior to the original peptide in terms of binding affinity as well as safety profile. MD results confirmed the stability, flexibility, reduced local motions, conformational changes, and more compact structure upon binding the receptor for 200 ns, which deserve in vitro validation as a better melanoma ACP therapeutic option. Conclusion These variants displayed increased flexibility, reduced conformational alterations and local motions, and a more compact configuration, suggesting greater stability compared with the reference peptide.