The MDM2-p53 protein-protein interaction is a validated oncology target, yet no food-derived linear peptide has been documented to engage the canonical three-anchor MDM2-p53 interface. We developed a multi-stage computational pipeline (PepVeg) to screen 22 plant and fungal proteomes (337,646 proteins) for MDM2-binding peptides, applying sequential in silico hydrolysis, physicochemical filtering, ESM-2 embedding-based dimensionality reduction, and pharmacophore-driven selection. Twenty-six candidates were evaluated by AlphaFold 3 (AF3) co-folding against MDM2(25-109), yielding 15 binders (iPTM >= 0.75; 58% of evaluated). A 36-peptide benchmark with 29 hard negatives confirmed AF3 discriminative power (Cohen's d = 3.41; 95% CI: 1.94-4.88; Hedges' g = 3.32; zero overlap). The lead candidate, SPAFESTWDILK -- a tryptic fragment of Zingiber officinale histone deacetylase (UniProt A0A8J5FLH2) -- was evaluated by eight computational assessments: AF3 Server (iPTM 0.83, SD 0.01), Protenix (iPTM 0.923), Chai-1 (iPTM 0.891), EvoEF2 (-55.57 EEU), two GROMACS simulations (no dissociation across two force fields), and two MM-PBSA calculations (-75.30 (SD 4.92) and -55.07 (SD 2.86) kcal/mol). The W8A point mutant produced an iPTM drop of 0.201, closely paralleling the p53 W23A drop of 0.193; we predict W8A substitution will abolish binding. SPAFESTWDILK ranked only #890/2,000 by ESM-2 similarity and was recovered solely through pharmacophore matching, demonstrating that no single pipeline stage alone is sufficient. To our knowledge, this is the first food-database-derived linear peptide with multi-convergent computational evidence supporting engagement of the canonical three-anchor MDM2-p53 interface. Experimental validation by SPR/ITC is warranted.
Ashtiani, M., Romiti, M., Sandri, C., Paiola, G.
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