Fast Peptide Ensemble Generation via a Hybrid Computational Pipeline: A Baseline Validation on the MDM2-p53 Interface

Peptide drug discovery is often bottlenecked by the immense computational cost of Molecular Dynamics (MD) simulations required to sample flexible conformations. Here, we present an unoptimized hybrid computational pipeline. By integrating a rapid heuristic search strategy in topological state space with a high-fidelity all-atom 3D geometric reconstruction algorithm, our engine generates high-affinity peptide conformers within seconds using only CPU. We demonstrate its baseline performance on the classic MDM2-p53 target (PDB: 1YCR). From a completely random initial state, the best generated conformer achieved a docking score of -20.15 kcal/mol, closely approaching the crystallographic ground truth of -22.92 kcal/mol (a gap of 2.77 kcal/mol). This baseline validation highlights the viability of this pipeline as an ultra-fast pre-filter for peptide drug discovery.