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Abstract
Existing protein-ligand docking methods computationally screen thousands to millions
of organic molecules against protein structures, trying to find those with complementary
shapes and highest binding free energies. To allow large molecular databases to be
screened rapidly, simple and approximative scoring functions are used as a fast filter,
resulting in low hit rates. Therefore, docking hit lists are commonly rescored in
a final step by more rigorous and time-consuming methods to gain a more accurate final
list of ranked compounds.
Molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) or generalized Born surface
area (MM-GBSA) methods are currently considered to be suitable techniques for rescoring.
These physically realistic approaches incorporate more sophisticated models for solvation
and electrostatic interactions than most scoring functions. Hence, they can discriminate
more reliably between correct and incorrect docking poses.
A high-throughput rescoring protocol using force field-based methods has been proposed
by Brown and Muchmore [1]. They used 18 in-house urokinase-ligand crystal structures
and their corresponding experimentally determined binding free energies as a test
set. On the basis of this rescoring protocol we tested several molecular dynamics
simulation protocols in combination with different MM-PBSA, and MM-GBSA calculation
procedures using Amber 10 [2] and Gromacs 4 [3]. Considering performance and accuracy,
our best rescoring protocol performs similarly to the one described by Brown and Muchmore
[1]. It has a comparable run-time and achieves a correlation between experimental
and rescored values of 0.88 compared to 0.87.
However, we used urokinase-ligand complexes generated using the docking program Glide
[4] instead of crystal structures. Additionally, this shows that our rescoring protocol
improves the correlation of 0.57 between experimental values and Glide scores significantly
to 0.88, thereby achieving a more accurate list of ranked compounds.
The protocol will be incorporated into BALLView [5], an open-source molecular viewer
and modeling tool. Thus, it will be available free of charge and can be conveniently
used to rescore (docked) protein-ligand complexes.