Blinded predictions of binding modes and energies of HSP90-α ligands for the 2015 D3R grand challenge |
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| Institution: | 2. Medtronic, Inc., Minneapolis, Minnesota;3. Cardiovascular Division, University of Minnesota, Minneapolis, Minnesota;4. Center for Cardiovascular Innovation, Feinberg School of Medicine, Northwestern University, Chicago, Illinois;1. Vorarlberg Institute for Vascular Investigation and Treatment (VIVIT), Feldkirch, Austria;2. Private University of the Principality of Liechtenstein, Triesen, Liechtenstein;3. Department of Medicine and Cardiology, Academic Teaching Hospital Feldkirch, Feldkirch, Austria;4. Medical Central Laboratories, Feldkirch, Austria;5. Drexel University College of Medicine, Philadelphia, PA, USA;1. Department of Chemistry, Payame Noor University, Tehran, Iran;2. Department of Chemistry, Faculty of Science, University of Sistan and Baluchestan, P.O. Box 98135-674, Zahedan, Iran;1. Graduate School of Medical Life Science, Yokohama City University, 1-7-29 Tsurumi, Yokohama 230-0045, Japan;2. Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo, Tokyo 113-8657, Japan |
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| 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. |
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| Keywords: | Computer-aided drug design Protein–ligand interactions Docking Ranking Scoring Alchemical free energy calculations |
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