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 angstrom 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.

Automated summary

This study presents a reliable and accurate solution for protein-ligand binding by combining different docking methods, achieving a low root-mean-square deviation in over 90% of cases. The predicted ligand-receptor structures were accurate enough to enable predictive structure-based drug discovery for challenging targets, expanding the applicability of such methods.