Milk-derived bioactive peptides as prospective ERK2 inhibitors: A computational screening strategy toward anticancer...

ERK2 plays a crucial role in regulating cellular signaling in both pathological and normal conditions. ERK2 is indispensable in human development, but its overexpression significantly promotes the proliferation of carcinomas. One feasible approach to selective ERK2 suppression is focusing on protein-protein interactions, with an emphasis on peptide-based inhibition of the D-recruitment site (DRS). In this regard, the milk bioactive peptide database, a comprehensive database of peptide sequences derived from various species, was explored, and 108 peptides with known anticancer and antioxidant activities were subsequently selected and examined against ERK2 DRS. The performance of HADDOCK 2.4 software in predicting peptide-ERK2 docking modes was initially evaluated using accessible experimental data. Upon calculating the docking scores of the milk-derived peptides towards ERK2 DRS, the top-ranked peptides were advanced for molecular dynamic (MD) simulations, combined with binding energy (ΔG_binding) computations utilizing the MM-GBSA approach. According to the MM-GBSA//200 ns MD simulations, peptides 41 and 49 unveiled superior binding affinities compared to the reference peptide KIM-MAP3, with ΔG_binding values of -57.3, -52.8, and -51.5 kcal/mol, respectively. Radius of gyration and binding energy per-frame analyses further confirmed the structural and energetic stability of the identified peptides bound to ERK2 over 200 ns MD simulations. The predicted physicochemical features of the identified peptides suggested a favorable functional potential. Collectively, these in-silico outcomes proposed that peptides 41 and 49 may serve as promising ERK2 inhibitors, deserving further experimental validation.