Reliable and Accurate Solution to the Induced Fit Docking Problem for Protein–Ligand Binding

We present a reliable and accurate solution to the induced fit
docking problem for protein–ligand binding by combining ligand-based
pharmacophore docking, rigid receptor docking, and protein structure
prediction with explicit solvent molecular dynamics simulations. This
novel methodology in detailed retrospective and prospective testing
succeeded to determine protein–ligand binding modes with a
root-mean-square deviation within 2.5 Å in over 90% of cross-docking
cases. We further demonstrate these predicted ligand–receptor
structures were sufficiently accurate to prospectively enable predictive
structure-based drug discovery for challenging targets, substantially
expanding the domain of applicability for such methods.