Computational Investigation of Covalent Organic Pyrgos[n]cages as Potential Dual Modulators of VEGFR-2 D2-D3 domain and DNA Structural Interfaces

Abstract

Angiogenesis, driven by vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 domain D2-D3 (VEGFR-2D23) 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), a purely covalent organic cage with electronically adaptive π-stacked systems, capable of engaging the extracellular VEGFR-2D23 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-2D23 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-2D23 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 and DNA interfaces and highlight its potential to modulate VEGFR-2 D23 domain and DNA binding.