Rational Design of a Novel Anti-Cancer Hybrid Peptide Inhibiting the PI3K/AKT and CDK2 Signaling Pathways using...

Area of Science:

• Biochemistry and Molecular Biology
• Computational Chemistry
• Drug Discovery and Development

Background:

• Melittin (MLT) peptide shows promise in suppressing tumor progression by targeting apoptosis pathways.
• Clinical use of MLT is hindered by high cytotoxicity and poor cellular permeability.
• Aurein 1.2 (Aur1.2) is another peptide with potential therapeutic applications.

Purpose of the Study:

• To design and evaluate a hybrid peptide (AM1) combining MLT and Aur1.2 for enhanced anticancer efficacy.
• To investigate the molecular interactions and stability of AM1 with key cancer-related proteins (AKT1 and CDK2).
• To assess the membrane penetration capabilities of the AM1 peptide.

Main Methods:

• Design of a hybrid peptide (AM1) by fusing a truncated MLT with a modified truncated Aur1.2.
• Molecular docking to predict interactions with AKT1 and CDK2 proteins.
• Molecular dynamics simulations (200 ns) using VMD for structural stability analysis (RMSD, RMSF, DSSP).
• MM/GBSA calculations for binding thermodynamics.
• Coarse-grained (CG) simulations to evaluate membrane penetration.

Main Results:

• AM1 demonstrated specific binding interactions with key residues in AKT1 and CDK2 proteins.
• Molecular dynamics simulations confirmed the structural stability of AM1 and its complexes with AKT1 and CDK2 over 200 ns.
• AM1 exhibited favorable thermodynamic binding and successfully penetrated a model lipid membrane in silico.
• The hybrid peptide maintained its alpha-helical structure in the Aurein 1.2 region during simulations.

Conclusions:

• The designed hybrid peptide AM1 shows significant potential as an inhibitor of the PI3K/AKT and CDK2 signaling pathways.
• AM1 possesses favorable stability and membrane permeability characteristics for potential therapeutic applications.
• Further experimental validation is required to confirm the in silico findings for AM1 as an anticancer agent.