Abstract
Fibroblast growth factor receptor 4 (FGFR4), a member of the fibroblast growth factor receptor family, plays a crucial role in cell growth, differentiation, and tissue repair. Increased FGFR4 expression has been detected in various cancers, including lung, liver, kidney and pancreatic cancer, making it a potential drug target. In this study, we conducted a structure-based virtual screening campaign to identify potential FGFR4 inhibitors. The retained compounds were further filtered based on pan assay interference compounds (PAINS) and absorption, distribution, metabolism, excretion, and toxicity (ADME/T) properties, leading to the identification of two promising candidates: MFCD00832235 and MFCD00204244. Quantum mechanical (QM) calculations revealed a large Highest Occupied Molecular Orbital (HOMO) and the Lowest Unoccupied Molecular Orbital (LUMO) (HUMO-LUMO) gaps for both compounds, indicating high dynamic stability and low chemical reactivity. Moreover, the stability of MFCD00832235 and MFCD00204244 at the adenosine triphosphate (ATP)-binding site of FGFR4 was confirmed through molecular dynamics (MD) simulations. The molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) approach predicted favorable binding free energy values for both compounds with the target protein. In vitro assay revealed that MFCD00832235 and MFCD00204244 inhibited the growth of HepG2 cells with IC(50) values of 47.42 ± 12.93 µM and 77.83 ± 19.17 µM, respectively. Overall, this study suggested that MFCD00832235 and MFCD00204244 were potential FGFR4 inhibitors and may serve as start points for developing novel modulators of FGFR4 for cancer treatment, particularly hepatocellular carcinoma.