title: Predicting ligand binding modes from neural networks trained on protein-ligand interaction fingerprints.
abstract: We herewith present a novel approach to predict protein-ligand binding modes from the single two-dimensional structure of the ligand. Known protein-ligand X-ray structures were converted into binary bit strings encoding protein-ligand interactions. An artificial neural network was then set up to first learn and then predict protein-ligand interaction fingerprints from simple ligand descriptors. Specific models were constructed for three targets (CDK2, p38-α, HSP90-α) and 146 ligands for which protein-ligand X-ray structures are available. These models were able to predict protein-ligand interaction fingerprints and to discriminate important features from minor interactions. Predicted interaction fingerprints were successfully used as descriptors to discriminate true ligands from decoys by virtual screening. In some but not all cases, the predicted interaction fingerprints furthermore enable to efficiently rerank cross-docking poses and prioritize the best possible docking solutions.
authors.affiliation: Laboratory of Chemoinformatics, UMR 7177 University of Strasbourg/CNRS, 4 rue B. Pascal, 67000 Strasbourg, France.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Chupakhin
authors.forename: Gilles
authors.initials: G
authors.lastname: Marcou
authors.forename: Igor
authors.initials: I
authors.lastname: Baskin
authors.forename: Alexandre
authors.initials: A
authors.lastname: Varnek
authors.forename: Didier
authors.initials: D
authors.lastname: Rognan
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D051357:Cyclin-Dependent Kinase 2 / Q000737:chemistry*; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D048308:Mitogen-Activated Protein Kinase 14 / Q000737:chemistry*; D062105:Molecular Docking Simulation; D016571:Neural Networks, Computer; D010449:Peptide Mapping / Q000706:statistics & numerical data*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D021281:Quantitative Structure-Activity Relationship
chemical_list: D018841:HSP90 Heat-Shock Proteins; C533585:HSP90AA2P protein, human; D008024:Ligands; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D048308:Mitogen-Activated Protein Kinase 14