Engineering of the Melanoma Inhibitor of Apoptosis (ML-IAP) Anticancer Peptide Through Comprehensive In Silico
Haitham Ahmed Al-Madhagi1, Muhammad Shahab2,3, Zheng Guojun3
1Biochemical Technology Program, Thamar University, Dhamar, Yemen, thuniv.net.
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.
Insights
Engineered anticancer peptides (ACPs) show improved binding affinity and safety for melanoma treatment. These novel peptide variants offer a promising therapeutic option for melanoma, warranting further in vitro validation.
Area of Science:
- Biochemistry
- Computational Biology
- Oncology
Background:
- Melanoma is a highly malignant skin cancer with significant mortality.
- Anticancer peptides (ACPs) are emerging as potent, biocompatible therapeutics with fewer side effects.
- Melanoma inhibitor of apoptosis (ML-IAP) is a key therapeutic target, currently inhibited by the nonapeptide AVPIAQKSE.
Purpose of the Study:
- To enhance the binding affinity and safety profile of the AVPIAQKSE peptide through in silico peptide engineering.
- To identify novel peptide variants with improved therapeutic potential against melanoma.
Main Methods:
- Downloaded and prepared the 3D structure of ML-IAP (PDB ID: 1OXQ).
- Identified hotspot residues and performed saturation mutagenesis to discover beneficial amino acid substitutions.
- Utilized HPEPDOCK 2 for docking, ToxIBTL and AllerCatPro 2 for safety assessment, and molecular dynamics simulations for stability analysis.
Main Results:
- Identified HVPIAQKSE, WVPWAQKSE, and HVPWAQKSE as superior mutants with enhanced binding affinity and safety.
- Molecular dynamics simulations confirmed the stability, flexibility, and more compact structure of the engineered peptides upon receptor binding.
Conclusions:
- The engineered peptide variants demonstrate improved stability and therapeutic potential compared to the original peptide.
- These novel ACPs represent a promising avenue for melanoma treatment and require in vitro validation.
