Disulfide-rich polysulfur alkaloids target vascular endothelial growth factor A through electronic duality and...

Vascular endothelial growth factor A (VEGFA) is a pivotal driver of tumor-induced angiogenesis, yet its flat and featureless interface has long resisted small-molecule intervention. Here, we report the first systematic exploration of disulfide-rich polysulfur alkaloids, lissoclibadins (LCs), as a promising candidate for VEGFA inhibitors. Comprehensive structural, electronic, and molecular dynamics analyses reveal that the sulfur-enriched cores of LCs confer conformational plasticity and electronic duality, enabling shape-responsive recognition of VEGFA loop regions. Quantum chemical descriptors highlight pronounced ambiphilicity at sulfur centers, with LC1, LC4, LC7, and LC8 displaying elongated S-S bonds, low bond strength indices, and high softness, correlating with enhanced reactivity and VEGFA engagement. Docking and simulation studies demonstrate stable binding of selected LCs at VEGFA's flexible loops, reinforced by sulphur-centered hydrogen bonds, dispersion interactions, and persistent hydrogen-bonding networks. Free-energy calculations identify LC7 (ΔH_total = - 38.9 ± 3.8 kcal·mol^-1) as the most potent binder, supported by favorable van der Waals and polar contributions. These findings establish LCs as the first small-molecule scaffolds to effectively target VEGFA and highlight electronic duality and shape responsiveness as powerful strategies for drugging "undruggable" protein-protein interfaces.