Multitarget Antihypertensive Potential of Bioactive Compounds From Centella asiatica, Justicia gendarussa, and Imperata cylindrica: An Integrated In Vitro and Molecular Docking Approach

Background: Hypertension is a leading global health challenge. It has been a major risk factor for cardiovascular disease events that contribute broadly to morbidity and mortality worldwide. With increasing life expectancy and changes in lifestyle and diet, the prevalence of hypertension has increased by up to 40% in certain parts of Asia, particularly in low- and middle-income countries (LMICs). The combination of Centella asiatica (C) leaves, Justicia gandarussa (J) leaves, and Imperata cylindrica (I) roots has been used to treat hypertension. Objective: To identify potential active substances that lower blood pressure, bioactive compounds from CJI were isolated and characterized in vitro, and in silico predictions were generated. Active compounds were identified with LC-HRMS. Methods: We hypothesized that the active compounds of CJI act as multitarget antihypertensives by inhibiting protein targets in the renin-angiotensin-aldosterone system (RAAS), including aspartic proteinase renin (2V0Z), Angiotensin-Converting Enzyme (ACE, 1R4L), angiotensin receptor (AT1R), and mineralocorticoid receptor (MR, 2AA2). LC-HRMS analysis identified 42 active compounds from CJI. Results: Ethanol extract of CJI showed antioxidant activity with an IC50 of 187,866 ppm. Our results indicated that various active substances in CJI could bind to different drug targets. For renin, cylindrin, and friedelin, binding affinities of -11 and -10.2 kcal/mol were observed at the S3 binding site, potentially blocking renin activity. For ACE, castillicetin and 1,5-dicaffeoylquinic acid exhibited binding affinities of -10.5 and -10.4 kcal/mol, respectively, and bound to its binding pocket. For AT1R, fernenol and friedelin had binding affinities of around -11 kcal/mol within the binding pocket. Regarding MR, only cylindrin could bind, with an affinity of -8.8 kcal/mol. Conclusion: the CJI combination shows promise as an alternative treatment for hypertension, likely inhibiting multiple drug targets in the RAAS pathway.