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D3R grand challenge 4: blind prediction of protein–ligand poses, affinity rankings, and relative binding free energies

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The Drug Design Data Resource (D3R) aims to identify best practice methods for computer aided drug design through blinded ligand pose prediction and affinity challenges. Herein, we report on the results of Grand Challenge 4 (GC4). GC4 focused on proteins beta secretase 1 and Cathepsin S, and was run in an analogous manner to prior challenges. In Stage 1, participant ability to predict the pose and affinity of BACE1 ligands were assessed. Following the completion of Stage 1, all BACE1 co-crystal structures were released, and Stage 2 tested affinity rankings with co-crystal structures. We provide an analysis of the results and discuss insights into determined best practice methods.

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This work was supported by National Institutes of Health (NIH) Grant 1U01GM111528 for the Drug Design Data Resource (D3R). We also thank OpenEye Scientific Software for generously donating the use of their software. We thank Prof. William Jorgensen (Yale) for providing valuable insight into the selected free energy sets. The RCSB PDB is jointly funded by the National Science Foundation (DBI-1832184), the National Institutes of Health (R01GM133198), and the United States Department of Energy (DE-SC0019749).The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the federal funding agencies. MKG has an equity interest in, and is a co-founder and scientific advisor of, VeraChem LLC; REA has equity interest in and is a co-founder and scientific advisor of Actavalon, Inc.; and PW has an equity interest in Relay Pharmaceuticals, Inc. We also thank the reviewers for their helpful suggestions.

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Correspondence to Rommie E. Amaro or Michael K. Gilson.

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Parks, C.D., Gaieb, Z., Chiu, M. et al. D3R grand challenge 4: blind prediction of protein–ligand poses, affinity rankings, and relative binding free energies. J Comput Aided Mol Des 34, 99–119 (2020). https://doi.org/10.1007/s10822-020-00289-y

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  • D3R
  • Docking
  • Scoring
  • Ligand ranking
  • Free-energy
  • Blinded prediction challenge