Targeting the ERK2 D-Recruitment Site with Anticancer Peptides from the DRAMP Database: An Integrated In Silico Study

ERK2 is a central regulator of the MAPK pathway, governing cell proliferation, differentiation, and survival, and its aberrant activation is a recognized driver of cancer progression. ATP-competitive ERK2 inhibitors suffer from limited selectivity owing to the highly conserved kinase active site, whereas the ERK2 D-recruitment site (DRS), a non-catalytic docking surface mediating substrate recruitment, offers a more selective route to pathway modulation. Herein, the DRAMP database was screened, yielding 31 peptides with putative anticancer activity within the 5–15 residue range, which were docked towards the ERK2 DRS employing HADDOCK2.4. The protocol was first validated by reproducing the crystallographic binding mode of the co-crystallized KIM-MAP3 peptide. Peptides meeting the applied docking-score threshold were advanced to molecular dynamics simulations, followed by MM-GBSA binding energy calculations. Over 200 ns trajectories, DRAMP03987, DRAMP03983, and DRAMP03985 bound ERK2 more favorably than the reference KIM-MAP3 peptide, with ΔGbinding values of −71.2, −65.1, and −63.1 kcal/mol, respectively, versus −51.5 kcal/mol. Energetic and structural analyses indicated sustained occupancy of the DRS throughout the simulations, while in silico physicochemical profiling revealed preliminary physicochemical characteristics. Collectively, these findings highlight the potential of the identified peptides as ERK2 DRS-binding candidates, warranting further experimental investigation.