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

Abstract

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.