Targeting the ERK2 Signaling Pathway With Frog Skin-Derived Bioactive Peptides: Insights From Molecular Modeling, Molecular Dynamics, and Physicochemical Features.

ERK2 plays a vital function in promoting cell survival and proliferation by phosphorylating various substrates. ERK2 is a key druggable target owing to its function in uncontrolled cell proliferation and cancer, making selective ERK2 inhibitors essential for treating aggressive malignancies. Peptides are promising therapeutic agents with strong biological activity, and frog skin-derived peptides have shown notable anticancer potential. Seventeen curated frog skin-derived anticancer peptides were modeled and docked against the ERK2 D-recruitment site (DRS) using HADDOCK2.4 software. The predicted peptide-DRS complexes were introduced to molecular dynamics simulations (MDS), and their binding energies (ΔGbinding) were evaluated utilizing the MM/GBSA approach. Upon MM/GBSA//200 ns MDS, dermaseptin-B3, dermaseptin-PD-1, and ascaphin-8 showed better binding affinities against ERK2 DRS, with ΔGbinding values of -77.8, -74.1, and -56.7 kcal/mol, respectively, compared with the structurally resolved DRS-binding reference peptide KIM-MAP3 (ΔGbinding = -51.5 kcal/mol). Post-MD analyses, including binding energy per trajectory and RMSD analyses, affirmed the great stability of the identified peptides complexed with ERK2 DRS over 200 ns MDS. The predicted physicochemical features of the identified peptides indicated favorable functional potential. Collectively, these computational outcomes highlighted dermaseptin-B3, dermaseptin-PD-1, and ascaphin-8 as promising ERK2 DRS-binding candidates. Further experimental validation is required to confirm their functional inhibitory activity.