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
ChemRxiv, 2020,03
https://chemrxiv.org/articles/A_Reliable_and_Accurate_Solution_to_the_Induced_Fit_Docking_Problem_for_Protein-Ligand_Binding/11983845/1?file=22003809

Abstract

We present a reliable and accurate solution to the induced fit docking problem for protein-ligand binding by combining ligand-based pharmacophore docking (Phase), rigid receptor docking (Glide), and protein structure prediction (Prime) with explicit solvent molecular dynamics simulations. We provide an in-depth description of our novel methodology and present results for 41 targets consisting of 415 cross-docking cases divided amongst a training and test set. For both the training and test-set, we compute binding modes with a ligand-heavy atom RMSD to within 2.5 Å or better in over 90% of cross-docking cases compared to less than 70% of cross-docking cases using our previously published induced-fit docking algorithm and less than 41% using rigid receptor docking. Applications of the predicted ligand-receptor structure in free energy perturbation calculations is demonstrated for both public data and in active drug discovery projects, both retrospectively and prospectively.