title: D3R grand challenge 2015: Evaluation of protein-ligand pose and affinity predictions.
abstract: The Drug Design Data Resource (D3R) ran Grand Challenge 2015 between September 2015 and February 2016. Two targets served as the framework to test community docking and scoring methods: (1) HSP90, donated by AbbVie and the Community Structure Activity Resource (CSAR), and (2) MAP4K4, donated by Genentech. The challenges for both target datasets were conducted in two stages, with the first stage testing pose predictions and the capacity to rank compounds by affinity with minimal structural data; and the second stage testing methods for ranking compounds with knowledge of at least a subset of the ligand-protein poses. An additional sub-challenge provided small groups of chemically similar HSP90 compounds amenable to alchemical calculations of relative binding free energy. Unlike previous blinded Challenges, we did not provide cognate receptors or receptors prepared with hydrogens and likewise did not require a specified crystal structure to be used for pose or affinity prediction in Stage 1. Given the freedom to select from over 200 crystal structures of HSP90 in the PDB, participants employed workflows that tested not only core docking and scoring technologies, but also methods for addressing water-mediated ligand-protein interactions, binding pocket flexibility, and the optimal selection of protein structures for use in docking calculations. Nearly 40 participating groups submitted over 350 prediction sets for Grand Challenge 2015. This overview describes the datasets and the organization of the challenge components, summarizes the results across all submitted predictions, and considers broad conclusions that may be drawn from this collaborative community endeavor.
authors.affiliation: Drug Design Data Resource, Center for Research in Biological Systems, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
authors.forename: Symon
authors.initials: S
authors.lastname: Gathiaka
authors.affiliation: Drug Design Data Resource, Center for Research in Biological Systems, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
authors.forename: Shuai
authors.initials: S
authors.lastname: Liu
authors.affiliation: Drug Design Data Resource, Center for Research in Biological Systems, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Chiu
authors.affiliation: RCSB Protein Data Bank, Center for Integrative Proteomics Research, Institute for Quantitative Biomedicine, Department Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, 174 Frelinghuysen Road, Piscataway, NJ, 08854, USA.
authors.forename: Huanwang
authors.initials: H
authors.lastname: Yang
authors.affiliation: Center for Structural Biology, Life Sciences Institute, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI, 48109-2216, USA.
authors.forename: Jeanne A
authors.initials: JA
authors.lastname: Stuckey
authors.affiliation: Center for Structural Biology, Life Sciences Institute, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI, 48109-2216, USA.
authors.forename: You Na
authors.initials: YN
authors.lastname: Kang
authors.affiliation: Center for Structural Biology, Life Sciences Institute, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI, 48109-2216, USA.
authors.forename: Jim
authors.initials: J
authors.lastname: Delproposto
authors.affiliation: Center for Structural Biology, Life Sciences Institute, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI, 48109-2216, USA.
authors.forename: Ginger
authors.initials: G
authors.lastname: Kubish
authors.affiliation: Department of Medicinal Chemistry, University of Michigan, 428 Church St., Ann Arbor, MI, 48109-1065, USA.
authors.forename: James B
authors.initials: JB
authors.lastname: Dunbar
authors.affiliation: Department of Medicinal Chemistry, University of Michigan, 428 Church St., Ann Arbor, MI, 48109-1065, USA.
authors.forename: Heather A
authors.initials: HA
authors.lastname: Carlson
authors.affiliation: RCSB Protein Data Bank, Center for Integrative Proteomics Research, Institute for Quantitative Biomedicine, Department Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, 174 Frelinghuysen Road, Piscataway, NJ, 08854, USA.|Department of Pharmacy, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.|San Diego Supercomputer Center, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
authors.forename: Stephen K
authors.initials: SK
authors.lastname: Burley
authors.affiliation: Relay Therapeutics, 215 First St, Cambridge, MA, 20142, USA.
authors.forename: W Patrick
authors.initials: WP
authors.lastname: Walters
authors.affiliation: Drug Design Data Resource, Center for Research in Biological Systems, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA. drugdesigndata@gmail.com.|Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA. drugdesigndata@gmail.com.
authors.forename: Rommie E
authors.initials: RE
authors.lastname: Amaro
authors.affiliation: Drug Design Data Resource, Center for Research in Biological Systems, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA. victoria.feher@schrodinger.com.|Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA. victoria.feher@schrodinger.com.|Schrodinger, Inc., New York, NY, USA. victoria.feher@schrodinger.com.
authors.forename: Victoria A
authors.identifier: 0000-0001-9899-8304
authors.initials: VA
authors.lastname: Feher
authors.affiliation: Drug Design Data Resource, Center for Research in Biological Systems, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA. mgilson@ucsd.edu.|Department of Pharmacy, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA. mgilson@ucsd.edu.|Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA. mgilson@ucsd.edu.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Gilson
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry*; D008024:Ligands; D062105:Molecular Docking Simulation; D011485:Protein Binding; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship
chemical_list: D018841:HSP90 Heat-Shock Proteins; D008024:Ligands
keywords: D3R; Docking; Free energy; Ligand; Protein; Scoring