title: Docking and Scoring with Target-Specific Pose Classifier Succeeds in Native-Like Pose Identification But Not Binding Affinity Prediction in the CSAR 2014 Benchmark Exercise.
abstract: The CSAR 2014 exercise provided an important benchmark for testing current approaches for pose identification and ligand ranking using three X-ray characterized proteins: Factor Xa (FXa), Spleen Tyrosine Kinase (SYK), and tRNA Methyltransferase (TRMD). In Phase 1 of the exercise, we employed Glide and MedusaDock docking software, both individually and in combination, with the special target-specific pose classifier trained to discriminate native-like from decoy poses. All approaches succeeded in the accurate detection of native and native-like poses. We then used Glide SP and MedusaScore scoring functions individually and in combination with the pose-scoring approach to predict relative binding affinities of the congeneric series of ligands in Phase 2 of the exercise. Similar to other participants in the CSAR 2014 exercise, we found that our models showed modest prediction accuracy. Quantitative structure-activity relationship (QSAR) models developed for the FXa ligands using available bioactivity data from ChEMBL showed relatively low prediction accuracy for the CSAR 2014 ligands of the same target. Interestingly, QSAR models built with CSAR data only yielded Spearman correlation coefficients as high as ρ = 0.69 for FXa and ρ = 0.79 for SYK based on 5-fold cross-validation. Virtual screening of the DUD library using the FXa structure was successful in discriminating between active compounds and decoys in spite of poor ranking accuracy of the underlying scoring functions. Our results suggest that two of the three common tasks associated with molecular docking, i.e., native-like pose identification and virtual screening, but not binding affinity prediction, could be accomplished successfully for the CSAR 2014 challenge data set.
authors.affiliation: Laboratory for Molecular Modeling, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, and ‡Department of Biochemistry and Biophysics, School of Medicine, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
authors.forename: Regina
authors.initials: R
authors.lastname: Politi
authors.affiliation: Laboratory for Molecular Modeling, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, and ‡Department of Biochemistry and Biophysics, School of Medicine, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
authors.forename: Marino
authors.initials: M
authors.lastname: Convertino
authors.affiliation: Laboratory for Molecular Modeling, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, and ‡Department of Biochemistry and Biophysics, School of Medicine, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Popov
authors.affiliation: Laboratory for Molecular Modeling, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, and ‡Department of Biochemistry and Biophysics, School of Medicine, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
authors.forename: Nikolay V
authors.initials: NV
authors.lastname: Dokholyan
authors.affiliation: Laboratory for Molecular Modeling, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, and ‡Department of Biochemistry and Biophysics, School of Medicine, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
authors.forename: Alexander
authors.initials: A
authors.lastname: Tropsha
mesh_terms: D019985:Benchmarking; D004353:Drug Evaluation, Preclinical; D015951:Factor Xa / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D062105:Molecular Docking Simulation; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*; D021281:Quantitative Structure-Activity Relationship; D000072377:Syk Kinase / Q000737:chemistry / Q000378:metabolism; D014584:User-Computer Interface; D012359:tRNA Methyltransferases / Q000737:chemistry / Q000378:metabolism
chemical_list: D008024:Ligands; D011506:Proteins; D012359:tRNA Methyltransferases; D000072377:Syk Kinase; D015951:Factor Xa