Does Short Molecular Dynamics Rescoring Improve the Ranking of p38α Inhibitors over Docking? A Replicate Benchmark
- 1St.Xavier's College
Abstract
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 p38 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 {Delta}G. 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 {Delta}G (Spearman {rho} = 0.28 98% CI -0.15 to 0.62), as did replica averaged MM/GBSA energies ({rho} = 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 ({rho} = 0.96 between the two sets of scores; {rho} = 0.37 against experiment, -0.04 to 0.69). In an exploratory analysis, ligands size alone correlated with affinity ({rho} = 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.
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BibTeX
@misc{dhakal2026does,
title = {{Does Short Molecular Dynamics Rescoring Improve the Ranking of p38α Inhibitors over Docking? A Replicate Benchmark}},
author = {A. Dhakal and G. Chand},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.27.762277},
url = {https://www.biorxiv.org/content/10.64898/2026.10.27.762277v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Does Short Molecular Dynamics Rescoring Improve the Ranking of p38α Inhibitors over Docking? A Replicate Benchmark
AU - A. Dhakal
AU - G. Chand
PY - 2026
DA - 2026/10/27
PB - bioRxiv
DO - 10.64898/2026.10.27.762277
UR - https://www.biorxiv.org/content/10.64898/2026.10.27.762277v1
AB - 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 p38 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 {Delta}G. 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 {Delta}G (Spearman {rho} = 0.28 98% CI -0.15 to 0.62), as did replica averaged MM/GBSA energies ({rho} = 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 ({rho} = 0.96 between the two sets of scores; {rho} = 0.37 against experiment, -0.04 to 0.69). In an exploratory analysis, ligands size alone correlated with affinity ({rho} = 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.
ER -