title: Receptor-guided 3D-QSAR approach for the discovery of c-kit tyrosine kinase inhibitors.
abstract: Studies of the the three-dimensional quantitative structure-activity relationships for ninety-five c-kit tyrosine kinase inhibitors were performed. Based on a co-crystallized compound (1 T46), known inhibitors were aligned with c-kit by induced-fit docking, and multiple training/test set splitting was performed to validate the selected pharmacophore model. The best pharmacophore model consisted of five features: one hydrogen-bond donor and four aromatic rings. Reliable statistics were obtained (R(2) = 0.95, R(pred) (2) = 0.75), and the model was validated by using it to select c-kit inhibitors from a database; 82.1% of the hits it retrieved were active. Accordingly, our model can be reliably used to identify new c-kit inhibitors, and can provide useful information when designing new inhibitors.
authors: Dipartimento di Scienze e Tecnologie Molecolari e Biomolecolari, Sezione di Chimica Farmaceutica e Biologica, Università di Palermo, Via Archirafi 32, 90123 Palermo, Italy. annamaria.almerico@unipa.it
authors: Anna Maria
authors: AM
authors: Almerico
authors: Marco
authors: M
authors: Tutone
authors: Antonino
authors: A
authors: Lauria
mesh_terms: D055808:Drug Discovery; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D019009:Proto-Oncogene Proteins c-kit