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Abstract
State of the art docking algorithms predict an incorrect binding pose for about 50-70%
of all ligands when only a single fixed receptor conformation is considered. In many
more cases, lack of receptor flexibility results in meaningless ligand binding scores,
even when the correct pose is obtained. Incorporating conformational rearrangements
of the receptor binding pocket into predictions of both ligand binding pose and binding
score is crucial for improving structure-based drug design and virtual ligand screening
methodologies. However, direct modeling of protein binding site flexibility remains
challenging because of the large conformational space that must be sampled, and difficulties
remain in constructing a suitably accurate energy function. Here we show that using
multiple fixed receptor conformations, either experimentally determined by crystallography
or NMR, or computationally generated, is a practical shortcut that may improve docking
calculations. In several cases, such an approach has led to experimentally validated
predictions.