Milk-derived peptides 41 and 49 computationally identified as potent ERK2 inhibitors for anticancer therapy

ERK2 (Extracellular signal-regulated kinase 2) is a critical regulator of cellular signaling, but its overexpression significantly drives carcinoma proliferation. Current MAPK pathway inhibitors often lack specificity, leading to off-target effects and compensatory activation of upstream proteins like SOS, RAS, and RAF. A promising strategy for selective ERK2 suppression involves targeting its D-recruitment site (DRS) with peptide-based inhibitors, offering a path to develop highly specific anticancer therapeutics with reduced side effects.

Researchers computationally screened a comprehensive milk bioactive peptide database, selecting 108 peptides with known anticancer and antioxidant activities. The HADDOCK 2.4 software's ability to predict peptide-ERK2 docking modes was validated against experimental data. Subsequently, the top-ranked peptides based on docking scores were advanced for 200 ns molecular dynamic (MD) simulations. Binding energies (ΔGbinding) were then computed using the MM-GBSA approach to assess inhibitory potential against the ERK2 DRS.

Computational screening and MD simulations revealed that two specific milk-derived peptides, 41 and 49, exhibited superior binding affinities to the ERK2 DRS compared to the reference peptide KIM-MAP3. This suggests a strong potential for ERK2 inhibition.

Peptide 41 achieved a ΔGbinding of -57.3 kcal/mol, while peptide 49 showed -52.8 kcal/mol, both significantly outperforming the reference peptide KIM-MAP3's ΔGbinding of -51.5 kcal/mol.

Further analyses, including radius of gyration and binding energy per-frame, confirmed the structural and energetic stability of these identified peptides when bound to ERK2 throughout the 200 ns MD simulations. The predicted physicochemical features of peptides 41 and 49 also indicated a favorable functional potential, supporting their candidacy as promising ERK2 inhibitors.