Receptor-guided 3D-QSAR approach for the discovery of c-kit tyrosine kinase inhibitors
- Autori: ALMERICO, AM; TUTONE, M; LAURIA, A
- Anno di pubblicazione: 2012
- Tipologia: Articolo in rivista (Articolo in rivista)
- Parole Chiave: C-kit . 3D-QSAR . Kohonen maps . Induced-fit docking
- OA Link: http://hdl.handle.net/10447/64271
Studies of the the three-dimensional quantitative structure–activity relationships for ninety-five c-kit tyrosine kinase inhibitors were performed. Based on a cocrystallized 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 (R2=0.95, Rpred 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.