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

For 29 neutral p38 kinase inhibitors (PDB 3FLY), short MD MM/GBSA rescoring did not measurably improve ranking over AutoDock Vina, with a score difference of -0.03 (-0.50 to 0.43).

• Why it matters: Docking rescoring with MD and MM/GBSA is common, but its added value for closely related analog series is uncertain, especially when experimental affinities span only a narrow range.
• What they did: Each ligand was docked with three Vina seeds and simulated in two independent 20 ns AMBER99SB-ILDN/GAFF2/TIP3L GROMACS replicas; MM/GBSA used 251 frames per trajectory without entropy.
• The result: Vina and replica-averaged MM/GBSA energies both correlated weakly with experimental {Delta}G (Spearman {rho} = 0.28 and 0.24), and independent replicas varied by 3.3 kcal/mol on average, limiting resolution.

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