Stability-Driven Pose Prediction and Ligand Design via Contact Persistence Analysis from Molecular Dynamics Simulations

Highlights • Across 137 protein–ligand complexes (10 targets; 1.64-ms total simulation), 83.9% of top-ranked poses achieve a root-mean-square deviation ≤3.0 Å relative to experimental structures. • R -values linearly correlate with experimental p K d (0.40 to 0.94 across 4 targets), validating the stability–affinity relationship. • Functional group-level persistence pinpoints unstable moieties for stability-guided lead optimization, demonstrated using KRAS G12D inhibitors as a case study.