Prospective performance evaluation of selected common virtual screening tools. Case study: Cyclooxygenase (COX) 1 and 2
Autor: | Teresa, Kaserer, Veronika, Temml, Zsofia, Kutil, Tomas, Vanek, Premysl, Landa, Daniela, Schuster |
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Rok vydání: | 2014 |
Předmět: |
Models
Molecular Drug Evaluation Preclinical AA arachidonic acid PGE2 Prostaglandin E2 ECFP4 Extended-connectivity fingerprints 4 Docking Method comparison SEA Similarity Ensemble Approach MNA multilevel neighborhoods of atoms FCFP6 Functional-class fingerprints 6 HBD hydrogen bond donor Acc accuracy Tc Tanimoto coefficient Molecular Structure R ring feature NI negative ionizable feature XVOL exclusion volume GFA genetic function approximation Cyclooxygenase EE early enrichment HIV-1 human immunodeficiency virus 1 OEST ROCS OpenEye shape Tanimoto Original Article DES diethylstilbestrol TP true positive hits WOMBAT World of Molecular Bioactivity ACE angiotensin-converting enzyme FN false negative hits FP false positive hits KEGG Kyoto Encyclopedia of Genes and Genomes Structure-Activity Relationship Shape-based modeling C cation TN true negative hits Humans Cyclooxygenase Inhibitors ROCS Rapid Overlay of Chemical Structures SERMs selective estrogen receptor modulators Pharmacophore modeling Ar aromatic feature OE overall enrichment Dose-Response Relationship Drug MB metal binding feature OECS ROCS OpenEye ComboScore DUD Directory of Useful Decoys m. p. melting point COX cyclooxygenase H hydrophobic feature Cyclooxygenase 2 HBA hydrogen bond acceptor Cyclooxygenase 1 PASS Prediction of Activity Spectra for Substances A anion PDB Protein Databank 2D similarity-based search |
Zdroj: | European Journal of Medicinal Chemistry |
ISSN: | 1768-3254 |
Popis: | Computational methods can be applied in drug development for the identification of novel lead candidates, but also for the prediction of pharmacokinetic properties and potential adverse effects, thereby aiding to prioritize and identify the most promising compounds. In principle, several techniques are available for this purpose, however, which one is the most suitable for a specific research objective still requires further investigation. Within this study, the performance of several programs, representing common virtual screening methods, was compared in a prospective manner. First, we selected top-ranked virtual screening hits from the three methods pharmacophore modeling, shape-based modeling, and docking. For comparison, these hits were then additionally predicted by external pharmacophore- and 2D similarity-based bioactivity profiling tools. Subsequently, the biological activities of the selected hits were assessed in vitro, which allowed for evaluating and comparing the prospective performance of the applied tools. Although all methods performed well, considerable differences were observed concerning hit rates, true positive and true negative hits, and hitlist composition. Our results suggest that a rational selection of the applied method represents a powerful strategy to maximize the success of a research project, tightly linked to its aims. We employed cyclooxygenase as application example, however, the focus of this study lied on highlighting the differences in the virtual screening tool performances and not in the identification of novel COX-inhibitors. Graphical abstract Highlights • Selected common virtual screening tools were applied in parallel. • Top-ranked hits were investigated with bioactivity profiling tools. • Compounds were tested in vitro for COX activity. • The prospective performance of all applied programs was evaluated and compared. |
Databáze: | OpenAIRE |
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