Development and experimental validation of a docking strategy for the generation of kinase-targeted libraries
| Autor: | Romuald Baudelle, Claude Monteils, Laurence Simon, Rafael Gozalbes, Eric Sartori, Nicolas Froloff |
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| Rok vydání: | 2008 |
| Předmět: |
Virtual screening
Inhibitory potential Binding Sites Molecular model Kinase Chemistry In silico Phosphotransferases Negative control Quantitative Structure-Activity Relationship Experimental validation Combinatorial chemistry Small Molecule Libraries Pyrimidines Docking (molecular) Drug Discovery Molecular Medicine Enzyme Inhibitors Crystallization Hydrophobic and Hydrophilic Interactions |
| Zdroj: | Journal of medicinal chemistry. 51(11) |
| ISSN: | 0022-2623 |
| Popis: | A high-throughput docking strategy for the filtering of in silico compounds and the generation of kinase-targeted libraries is described. Systematic docking and scoring in three kinase crystal 3D structures of 123 structurally diverse kinase ligands led to the determination of six thresholds for each kinase. These thresholds were used as filters for the virtual screening of two collections of compounds: a collection of more than 2500 drugs and drug-like compounds (negative control) and a kinase-targeted library of 1440 compounds. This strategy was then experimentally validated by testing 60 compounds from the kinase-targeted library on 41 kinases from five different families. The 60 compounds were split into those passing all the thresholds and the others (30 compounds in each group). The overall hit enrichment was 6.70-fold higher in the first group, validating our approach for the generation of kinase-targeted libraries and the identification of scaffolds with high kinase inhibitory potential. |
| Databáze: | OpenAIRE |
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