Does Short Molecular Dynamics Rescoring Improve the Ranking of p38α Inhibitors over Docking? A Replicate Benchmark

Rescoring docked ligands with molecular dynamics (MD) and end point free energy methods such as MM/GBSA is widely used, but its benefit over docking for series of close analogs is uncertain. We compared AutoDock Vina scores with Md based MM/GBSA energies for 29 neutral p38α kinase inhibitors (PDB 3FLY) from the Open Force Field protein-ligand benchmark, whose IC50 values from a single publication span 3.8 kcal/mol in estimate ΔG. Each ligand was docked with three random seeds and simulated in two independent 20 ns replicas started from the benchmark pose (AMBER99SB-ILDN, GAFF2, TIP3L; GROMACS). MM/GBSA energies were calculated from 251 frames per trajectory without an entropy term. All 58 simulations remained stable with the ligand bound. Vina scores correlated weakly with experimental ΔG (Spearman ρ = 0.28 98% CI -0.15 to 0.62), as did replica averaged MM/GBSA energies (ρ = 0.24 -0.18 to 0.62). The difference was -0.03 (-0.50 to 0.43), so the methods were not distinguishable. Independent replicas of the same ligand differed by 3.3 kcal/mol on average, comparable to the experimental range. Raising the interior dielectric constant from 1 to 2 gave a nearly identical ranking (ρ = 0.96 between the two sets of scores; ρ = 0.37 against experiment, -0.04 to 0.69). In an exploratory analysis, ligands size alone correlated with affinity (ρ = 0.60, 0.28 to 0.82), whereas neither computed score tracked size. For this narrow range series, short MD rescoring gave no measurable improvement over docking, and replica variability limited its resolution.