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.

Theoretical and Experimental Elucidation of the Adsorption Process of a Bioinspired Peptide on Mineral Surfaces

“…These optimized coordinates were then heated from 0 to 100 K within the NVT MD protocol for 100 ps and switched to NTP for 1 ns in order to reach the desired temperature of 300 K. During this process, the surface is restrained through weak harmonic restraints of 5 kcal/mol. Other details about the MD protocol may be found elsewhere . After the heating process, all restraints were removed and MD productions were pursued in the NVT ensemble for 400 ns.…”

“…These two molecules were embedded in a water box and engaged within NTP MD for 10 ns. Determination of isotropic solvation energies was performed through an MMGBSA scheme which has proven its efficiency to provide meaningful values for protein/protein, protein/ligand, , nucleic acid/ligand, , and carbohydrate/carbohydrate. , Only the last 5 ns of trajectories was included for establishing the solvation energies. These last nanoseconds were determined every picosecond and finally averaged (see Table ).…”

“…Other details about the MD protocol may be found elsewhere. 45 After the heating process, all restraints were removed and MD productions were pursued in the NVT ensemble for 400 ns. VMD software 42 was employed to observe the MD trajectories and make figures.…”

Molecular Dynamics Simulation of a RNA Aptasensor

“…Indeed these structures exist only in the presence of their respective ligands and are folded by these ones. In the case of MMGBSA, only the interaction is computed and this method has proven its efficiency to provide meaningful values of binding free energies for protein/ligand systems, − DNA/ligand, RNA/ligand, and even carbohydrates systems. , Besides, the purpose of this article is not a quantitative description of RNA aptamer biosensor but a rough evaluation of the interaction energy of ligand using MM/GBSA. Therefore, perhaps the trend of binding energy could be accessible by this method, but the absolute values could include significant inaccuracy.…”

Adventures in cooperativity

“…Nevertheless, a review of the literature showed that the effect has been frequently invoked as a mechanism of inhibitor binding to kinases, sometimes alone and sometimes in combination with conformational selection. For example, it was shown for tyrosine kinases, that large scale motions generate a range of conformations, some capable of binding type II inhibitors, and then inducing further conformational change [47,48]. A recent elaborate reassessment of the binding of Gleevec™ (Imatinib) to c-Src kinase, using X-ray crystallography, dynamics simulations, NMR and Plasmon Surface Resonance concluded with considerable emphasis that "both conformational selection and induced fit play a role in the binding mechanism, reconciling opposing views held in the literature" [49].…”