D3R Grand Challenge 4: prospective pose prediction of BACE1 ligands with AutoDock-GPU

J Comput Aided Mol Des. 2019 Dec;33(12):1071-1081. doi: 10.1007/s10822-019-00241-9. Epub 2019 Nov 6.


In this paper we describe our approaches to predict the binding mode of twenty BACE1 ligands as part of Grand Challenge 4 (GC4), organized by the Drug Design Data Resource. Calculations for all submissions (except for one, which used AutoDock4.2) were performed using AutoDock-GPU, the new GPU-accelerated version of AutoDock4 implemented in OpenCL, which features a gradient-based local search. The pose prediction challenge was organized in two stages. In Stage 1a, the protein conformations associated with each of the ligands were undisclosed, so we docked each ligand to a set of eleven receptor conformations, chosen to maximize the diversity of binding pocket topography. Protein conformations were made available in Stage 1b, making it a re-docking task. For all calculations, macrocyclic conformations were sampled on the fly during docking, taking the target structure into account. To leverage information from existing structures containing BACE1 bound to ligands available in the PDB, we tested biased docking and pose filter protocols to facilitate poses resembling those experimentally determined. Both pose filters and biased docking resulted in more accurate docked poses, enabling us to predict for both Stages 1a and 1b ligand poses within 2 Å RMSD from the crystallographic pose. Nevertheless, many of the ligands could be correctly docked without using existing structural information, demonstrating the usefulness of physics-based scoring functions, such as the one used in AutoDock4, for structure based drug design.

Keywords: AutoDock; D3R; Docking; Drug design data resource; Macrocycle.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases / chemistry*
  • Amyloid Precursor Protein Secretases / ultrastructure
  • Aspartic Acid Endopeptidases / chemistry*
  • Aspartic Acid Endopeptidases / ultrastructure
  • Binding Sites / drug effects
  • Computer-Aided Design
  • Crystallography, X-Ray
  • Databases, Protein
  • Drug Design
  • Ligands
  • Macrocyclic Compounds / chemistry
  • Molecular Docking Simulation*
  • Protein Binding*
  • Protein Conformation*
  • Thermodynamics


  • Ligands
  • Macrocyclic Compounds
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human