Multi-Target Binding Profiles of Natural Polyphenols: Implications for Cellular Perfusion, Vascular Biology, and Cardiovascular Pathophysiology

Natural polyphenols have emerged as potential multi-target agents in cardiovascular diseases due to their regulatory effects on oxidative stress, inflammation, and vascular signaling pathways. In this study, the binding profiles of six natural polyphenolic compounds—apigenin, gallic acid, kaempferol, luteolin, quercetin, and rosmarinic acid—toward protein targets associated with cellular perfusion, endothelial biology, and cardiovascular pathophysiology were evaluated using molecular docking analysis. Molecular docking analyses were performed using the UCSF Chimera and AutoDock Vina software packages. Six target proteins selected from the Protein Data Bank database included hypoxia-inducible factor prolyl hydroxylase (PHD2), neuropilin-1 (NRP1), the HIF-2α/ARNT heterodimer, ADAMTS4, the VEGFR2 kinase domain, and the VEGF-A receptor-binding domain. Binding affinities were evaluated based on the lowest binding energy values (kcal/mol) obtained from poses with RMSD = 0. According to the obtained results, binding energies ranged between −3.9 and −8.9 kcal/mol. Quercetin exhibited the strongest overall binding profile, demonstrating particularly high affinity toward the ADAMTS4 and PHD2 targets. Other flavonoid compounds, especially luteolin and apigenin, also displayed strong and balanced binding affinities across multiple targets. Rosmarinic acid showed selectively high binding affinity particularly toward the NRP1 target, whereas gallic acid generally exhibited lower binding affinities. In conclusion, these findings suggest that natural polyphenols may modulate interconnected processes such as hypoxia response, endothelial function, vascular remodeling, and extracellular matrix regulation through multiple molecular targets. This multi-target potential indicates that these compounds may serve as functional and therapeutic candidates in the context of cellular perfusion and cardiovascular pathophysiology. However, further advanced in vitro and in vivo studies are required to validate these findings.