title: Blinded predictions of binding modes and energies of HSP90-α ligands for the 2015 D3R grand challenge.
abstract: In the framework of the 2015 D3R inaugural grand challenge, blind binding pose and affinity predictions were performed for a set of 180 ligands of the Heat Shock Protein HSP90-α protein, a relevant cancer target. Spectral clustering was used to rapidly identify alternative binding site conformations in publicly available crystallographic HSP90-α structures. Subsequently, multiple docking and scoring protocols employing the software Autodock Vina and rDock were applied to predict binding modes and rank order ligands. Alchemical free energy calculations were performed with the software FESetup and Sire/OpenMM to predict binding affinities for three congeneric series subsets. Some of the protocols used here were ranked among the top submissions according to most of the evaluation metrics. Docking performance was excellent, but the scoring results were disappointing. A critical assessment of the results is reported, as well as suggestions for future similar competitions.
authors.affiliation: EaStCHEM School of Chemistry, University of Edinburgh, West Mains Road, Edinburgh EH9 3FJ, United Kingdom.
authors.forename: Antonia S J S
authors.initials: ASJS
authors.lastname: Mey
authors.affiliation: EaStCHEM School of Chemistry, University of Edinburgh, West Mains Road, Edinburgh EH9 3FJ, United Kingdom.
authors.forename: Jordi
authors.initials: J
authors.lastname: Juárez-Jiménez
authors.affiliation: EaStCHEM School of Chemistry, University of Edinburgh, West Mains Road, Edinburgh EH9 3FJ, United Kingdom.
authors.forename: Alexis
authors.initials: A
authors.lastname: Hennessy
authors.affiliation: EaStCHEM School of Chemistry, University of Edinburgh, West Mains Road, Edinburgh EH9 3FJ, United Kingdom. Electronic address: mail@julienmichel.net.
authors.forename: Julien
authors.initials: J
authors.lastname: Michel
mesh_terms: D001665:Binding Sites; D016208:Databases, Factual; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry*; D008024:Ligands; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D013816:Thermodynamics
chemical_list: D018841:HSP90 Heat-Shock Proteins; D008024:Ligands
keywords: Alchemical free energy calculations; Computer-aided drug design; Docking; Protein–ligand interactions; Ranking; Scoring