Network pharmacology and molecular docking analysis of propolis-derived bioactive compounds targeting antihypertensive pathways

Hypertension is a major global health problem associated with dysregulation of the renin-angiotensin system and vascular signaling pathways. Propolis has demonstrated antihypertensive activity; however, its active compounds and molecular targets have not been comprehensively elucidated. This study aimed to identify potential antihypertensive protein targets of propolis-derived compounds using an integrated network pharmacology and molecular docking approach. Propolis compounds were identified through LCHRMS analysis and screened for natural origin and toxicity using the COCONUT database and ProTox 3.0. Hypertension-related targets were collected from GeneCards and OMIM, while compound-associated targets were predicted using SwissTargetPrediction. Intersecting targets were analyzed through protein-protein interaction (PPI) networks and enrichment analysis. Key hub proteins were subjected to molecular docking with selected propolis compounds, followed by drug-likeness and pharmacokinetic prediction using SwissADME and pkCSM. Twenty-three propolis compounds with predicted low toxicity risk were identified after screening. Network pharmacology analysis identified 44 intersecting targets, refined to 29 hub proteins after exclusion of non-primary hypertension targets and network pruning, with ACE, REN, and PPARG identified as major hub proteins. Gene Ontology and KEGG pathway analyses highlighted the renin-angiotensin system and related cardiovascular pathways. Molecular docking demonstrated that naringenin (C2) and hesperetin (C14) exhibited favourable predicted binding affinities toward ACE, REN, and PPARG, comparable to those of the reference antihypertensive drugs docked under identical conditions, although lower than those of the co-crystallized native ligands. Both compounds showed favorable drug-likeness, high predicted intestinal absorption, and a predicted low toxicity risk. This study suggests that naringenin and hesperetin are candidate multitarget bioactive molecules from propolis with predicted antihypertensive potential. These findings provide a mechanistic basis for further in vitro and in vivo validation to support their therapeutic potential.