Computational investigation of covalent organic pyrgos[n]cages as potential dual modulators of the VEGFR-2 D2-D3 domain and DNA structural interfaces.

Angiogenesis, driven by vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 domain D2-D3 (VEGFR-2 D23) signaling, plays a central role in tumor vascularization and progression. In this multiscale computational study, we investigate pyrgos[n]cages (PC[n], n = 1-4), purely covalent organic cages with electronically adaptive π-stacked systems, capable of engaging the extracellular VEGFR-2 D23 ligand-binding interface (wild type and mutant) and DNA (duplex and fork) structures. Molecular dynamics simulations and electronic structure analyses indicate that the electronically soft and polarizable PC[2-4] frameworks preferentially localize within the VEGFR-2 D23 interdomain cleft, stabilized by hydrogen bonding, π⋯π stacking, and π⋯H interactions. This multivalent interaction pattern suggests potential steric interference with VEGF binding while preserving overall receptor structural stability, including mutant VEGFR-2 D23 variants. Complementary DNA-binding analyses reveal structurally stable groove-associated binding stabilized by directional hydrogen bonds, phosphate backbone interactions, π⋯π stacking, and van der Waals contacts. Among the studied systems, PC[4] exhibits the most favorable binding enthalpy estimates for VEGFR-2 D23 (-48.3 ± 3.5 kcal mol-1), mutant M-VEGFR-2 D23 (-24.3 ± 5.8 kcal mol-1), and duplex DNA (-44.8 ± 3.8 kcal mol-1). At the same time, PC[2] shows favorable interaction with fork DNA (-46.3 ± 4.5 kcal mol-1). These findings provide mechanistic insight into the organic cage PC[n] in engaging biologically relevant protein-DNA interfaces and highlight its potential to modulate the VEGFR-2 D23 domain and DNA binding.