AYUSH-HR formulation for hypertension: An in-silico network pharmacology and ensemble docking study

Hypertension remains one of the leading global risk factors for cardiovascular morbidity and mortality, affecting millions worldwide. Despite significant advances in pharmacotherapy, optimal blood pressure control remains challenging, necessitating the exploration of alternative and complementary therapeutic strategies. Traditional Indian systems of medicine describe several herbal formulations with potential antihypertensive effects. The present study investigates the mechanistic basis of the AYUSH-HR formulation, comprising phytoconstituents from Acorus calamus (Vacha), Bacopa monnieri (Brahmi), Nardostachys jatamansi (Jatamansi), and Terminalia arjuna (Arjuna), using an integrative network pharmacology and structure-based computational approach. Target identification was carried out through multiple prediction algorithms, followed by gene ontology and pathway enrichment analyses which indicated significant modulation of proteins involved in the renin-angiotensin system (RAS), a central regulator of blood pressure homeostasis. Key RAS components, angiotensin-converting enzyme (ACE), renin (REN), and angiotensin II type 1 receptor (AT1R) emerged as probable therapeutic targets. Molecular docking studies on these target proteins revealed that saponins derived from Bacopa monnieri exhibited strong binding affinities toward these targets. Given that AT1R is membrane-bound receptors that serve as primary molecular interfaces for antihypertensive agents, ensemble docking studies were performed on AT1R to account for receptor conformational flexibility. Notably, terflavin C from Terminalia arjuna and nardostachysin from Nardostachys jatamansi demonstrated robust binding to AT1R, forming a higher number of stabilizing interactions compared to other phytoconstituents. Nardostachysin exhibited interaction profiles comparable to clinically used AT1R inhibitors. Collectively, the findings suggest that saponins, terflavin C, and nardostachysin may function as active bioactive compounds within the AYUSH-HR formulation by targeting critical components of the renin-angiotensin pathway. These results provide a mechanistic rationale supporting its antihypertensive potential. Further experimental validation and clinical correlation studies are warranted to substantiate the therapeutic utility of AYUSH-HR as a complementary strategy for hypertension management.