Background: A high-throughput virtual screening pipeline has been extended from single
energetically minimized structure Molecular Mechanics/Generalized Born Surface Area (MM/GBSA)
rescoring to ensemble-average MM/GBSA rescoring. The correlation coefficient (R2) of calculated
and experimental binding free energies for a series of antithrombin ligands has been improved from
0.36 to 0.69 when switching from the single-structure MM/GBSA rescoring to ensemble-average one.
The electrostatic interactions in both solute and solvent are identified to play an important role in determining
the binding free energy after the decomposition of the calculated binding free energy. The
increasing negative charge of the compounds provides a more favorable electrostatic energy change
but creates a higher penalty for the solvation free energy. Such a penalty is compensated by the electrostatic
energy change, which results in a better binding affinity. A highly hydrophobic ligand is determined
by the docking program to be a non-specific binder.
Results: Our results have demonstrated that it is very important to keep a few top poses for rescoring,
if the binding is non-specific or the binding mode is not well determined by the docking calculation.
Keywords: Docking, MM/GBSA, Rescoring, VinaLC, BINDSURF, Binding Affinity, Molecular Dynamics, Antithrombin.
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