Selective Inhibition of VEGFR2 in Preference to Other Receptor Tyrosine Kinases by Diosgenin, a Natural Steroidal...

This study aimed to assess the ability of diosgenin and its derivatives to suppress three angiogenic receptor tyrosine kinases-VEGFR2, FGFR1, and PDGFRA-through comprehensive in silico screening, molecular docking, and molecular dynamics simulations.

We screened 1,525 plant-derived compounds, 20 sapogenins, and three diosgenin derivatives for drug-likeness and bioavailability using SwissADME. The top candidates were docked against the three receptor tyrosine kinases using PyRx. Diosgenin and 14 of its derivatives were then further analyzed. Molecular dynamics simulations were performed using NAMD3 with CHARMM force fields to assess the stability of the protein-ligand complexes. Parameters such as RMSD, RMSF, Rg, and ΔG were evaluated.

Diosgenin was among the top 10 hits for all three receptor tyrosine kinases. It showed the strongest binding and stable interactions with VEGFR2 (ΔG:  -11.03 kcal/mol) compared to lenvatinib (ΔG: -7.52 kcal/mol) and sorafenib (ΔG: -4.01 kcal/mol). The FGFR1-diosgenin and PDGFRA-Diosgenin complexes displayed positive ΔG values, indicating less favorable thermodynamic binding. Three diosgenin derivatives (Formosanin C, Dioscin, and 2-Amin-5-(4-pyridyl)-1,3,4-thiadiazole DG-8d moiety) were also evaluated for their anticancer potential. While Formosanin C showed the highest binding affinities among all three derivatives, diosgenin uniquely interacted with the key catalytic residues of VEGFR2, suggesting functionally more relevant inhibition despite slightly lower docking scores. Similarly, Yamogenin, another sapogenin evaluated, exhibited a high binding affinity across all three angiogenic receptors. Although Yamogenin showed high affinity across all three receptors, molecular dynamics confirmed the superior stability of diosgenin with VEGFR2 (ΔG = -11.03 vs. -9.85 kcal/mol).

Diosgenin represents a promising and selective VEGFR2 inhibitor with  potential to have anti-angiogenic therapeutic activity.