title: Molecular modeling study of the induced-fit effect on kinase inhibition: the case of fibroblast growth factor receptor 3 (FGFR3).
abstract: Tyrosine kinases are a wide family of targets with strong pharmacological relevance. These proteins undergo large-scale conformational motions able to inactivate them. By the end of one of these structural processes, a new cavity is opened allowing the access to a specific type of inhibitors, called type II. The kinase domain of fibroblast growth factor receptor 3 (FGFR3) falls into this family of kinases. We describe here, for the first time, its inactivation process through target molecular dynamics. The transient cavity, at the crossroad between the DFGout and Cα helix out inactivation is herein explored. Molecular docking calculations of known ligands demonstrated that type II inhibitors are able to interact with this metastable transient conformation of FGFR3 kinase. Besides, supplemental computations were conducted and clearly show that type II inhibitors drive the kinase inactivation process through specific stabilization with the DFG triad. This induced-fit effect of type II ligands toward FGFR3 might be extrapolated to other kinase systems and provides meaningful structural information for future drug developments.
authors: Department of Chemistry, Lanzhou University, Lanzhou, 730000, Gansu, People's Republic of China.
authors: Yan
authors: Y
authors: Li
authors: Michel
authors: M
authors: Delamar
authors: Patricia
authors: P
authors: Busca
authors: Guillaume
authors: G
authors: Prestat
authors: Laurent
authors: L
authors: Le Corre
authors: Laurence
authors: L
authors: Legeai-Mallet
authors: RongJing
authors: R
authors: Hu
authors: Ruisheng
authors: R
authors: Zhang
authors: Florent
authors: F
authors: Barbault
mesh_terms: D008024:Ligands; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D015203:Reproducibility of Results
chemical_list: D008024:Ligands; D047428:Protein Kinase Inhibitors; D051498:Receptor, Fibroblast Growth Factor, Type 3