Docking covalent inhibitors: a parameter free approach to pose prediction and scoring

J Chem Inf Model. 2014 Jul 28;54(7):1932-40. doi: 10.1021/ci500118s. Epub 2014 Jun 26.


Although many popular docking programs include a facility to account for covalent ligands, large-scale systematic docking validation studies of covalent inhibitors have been sparse. In this paper, we present the development and validation of a novel approach for docking and scoring covalent inhibitors, which consists of conventional noncovalent docking, heuristic formation of the covalent attachment point, and structural refinement of the protein-ligand complex. This approach combines the strengths of the docking program Glide and the protein structure modeling program Prime and does not require any parameter fitting for the study of additional covalent reaction types. We first test this method by predicting the native binding geometry of 38 covalently bound complexes. The average RMSD of the predicted poses is 1.52 Å, and 76% of test set inhibitors have an RMSD of less than 2.0 Å. In addition, the apparent affinity score constructed herein is tested on a virtual screening study and the characterization of the SAR properties of two different series of congeneric compounds with satisfactory success.

MeSH terms

  • Crystallography, X-Ray
  • Drug Discovery / methods*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology
  • Ligands
  • Molecular Docking Simulation*
  • Protein Conformation
  • Structure-Activity Relationship


  • Enzyme Inhibitors
  • Ligands