Structure-Based Molecular Docking Study of a Designed Cationic Peptide Sequence KRLVAGLIRKLA Against Targeting the Extracellular Domain of HER2 in HER2-Positive Breast Cancer

Abstract

Overexpression of the human epidermal growth factor receptor 2 (HER2) protein occurs in a significant number of breast cancers and serves as a validated therapeutic target but suffers from the problems of resistance, expense and toxicity when using an antibody for this purpose. Peptides present a more compact, economical alternative. In this study, a 12-residue cationic peptide, KRLVAGLIRKLA (charge +4), was studied as a ligand of the extracellular domain of HER2 (PDB ID 3MZW) through molecular docking with AutoDock 4.2.6 in 100 runs using the Lamarckian genetic algorithm. These 100 runs were organized into 60 clusters of conformation and had estimated binding energies between −9.82 and −3.15 kcal/mol (average −6.07 ± 1.42 kcal/mol). The most favorable pose (run 58; −9.82 kcal/mol; predicted Ki 63.7 nM) came from the biggest cluster (10 runs) and formed two salt bridges (Lys1–Asp395 and Lys10–Glu373) and three directional hydrogen bonds, interacting with 98 atom pairs within 4 Å of 13 HER2 residues. .  While van der Waals, hydrogen bonds, and desolvation energy accounted for much more of the variance in the score compared to electrostatics (Spearman ρ = 0.79 versus 0.61), compared to the 26-amino-acid binding area of the affibody Z(HER2:342) crystallized in complex, the top-scoring docking poses were located towards the edge of this binding area and shared only four amino acids with it. In conclusion, the docking results support peptide binding in the vicinity of the affibody side of HER2 but do not provide any evidence of the specific and stable binding.