Multiple binding modes of the tyrosine kinase inhibitor dovitinib to fibroblast growth factor receptor 1 characterized by surface plasmon resonance, 19F-NMR, and molecular dynamics simulations

Fibroblast growth factor receptor 1 (FGFR1) is a receptor-type tyrosine kinase involved in various human cancers, making it an attractive therapeutic target. To elucidate the complex binding dynamics between FGFR1 and its highly selective inhibitor, dovitinib, we conducted a detailed investigation using a combination of surface plasmon resonance (SPR), 19F-NMR spectroscopy, and molecular dynamics (MD) simulations. Kinetic analysis using SPR suggested that the interaction between FGFR1 and dovitinib is better described by a two-state binding model, implying the potential formation of an initial transient intermediate prior to the formation of a stable complex. We further characterized this interaction using 19F-NMR by leveraging the intrinsic fluorine atoms of dovitinib. When dovitinib was present in excess relative to FGFR1, the 19F-NMR signal exhibited broadening compared to that in the free state, indicating altered dovitinib environments and additional FGFR1-associated states. Furthermore, MD simulations introducing an additional dovitinib molecule to the FGFR1-dovitinib complex indicated the potential for weak and transient interactions in the preferred interaction regions on the FGFR1 surface. These findings highlight the multifaceted nature of kinase-inhibitor interactions and provide valuable biophysical insights that may contribute to future drug discovery efforts targeting receptor tyrosine kinases.