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

• DOI: 10.1021/acs.jctc.1c00136
• Publication Date: 2021-03-29T12:33:36Z
• Authors: Edward B. Miller; Robert B. Murphy; Daniel Sindhikara; Kenneth W. Borrelli; Matthew J. Grisewood; Fabio Ranalli; Steven L. Dixon; Steven Jerome; Nicholas A. Boyles; Tyler Day; Phani Ghanakota; Sayan Mondal; Salma B. Rafi; Dawn M. Troast; Robert Abel; Richard A. Friesner
• Keywords: Docking (animal); Protein–ligand docking

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 protein structure prediction with explicit solvent molecular dynamics simulations. This novel methodology in detailed retrospective prospective testing succeeded determine modes root-mean-square deviation within 2.5 Å over 90% of cross-docking cases. further demonstrate these predicted ligand–receptor structures were sufficiently prospectively enable predictive structure-based drug discovery challenging targets, substantially expanding domain applicability such methods.