Computational Evaluation of Nypa fruticans Phytochemicals as ACE Inhibitors Against Hypertension and Chronic Kidney Disease

ABSTRACT Oxidative stress and hyperactivation of the renin‒angiotensin‒aldosterone system (RAAS) accelerates the progression of chronic kidney disease (CKD), a global health burden. Angiotensin‐converting enzyme (ACE) is a key therapeutic target for CKD. This study uses a computational approach to evaluate Nypa fruticans (NF) as a natural ACE inhibitor. HPLC and GC‒MS analysis identified 36 compounds in NF extracts, with quercetin, rosmarinic acid, and caffeic acid as key bioactive compounds. Pharmacokinetic and toxicity evaluations via SwissADME, pkCSM, and ProTox 3.0, confirmed their drug‐likeness and safety profiles. Molecular docking studies revealed that quercetin and rosmarinic acid exhibited binding affinities of −8.28 and −8.95 kcal/mol with ACE (PDB: 1O86), respectively, outperforming the control, enalapril (−8.1 kcal/mol). Density functional theory (DFT) analysis revealed that rosmarinic acid (0.1342 eV) presented an energy gap similar to that of enalapril (0.1488 eV). In contrast, quercetin presented greater electrophilicity (0.2166 vs. 0.0853 eV), indicating a stronger electron‐accepting potential. Additionally, 100‐ns molecular dynamics simulations and MM‐GBSA analysis confirmed the stable binding of quercetin and rosmarinic acid, supporting their potential as natural antihypertensive agents for CKD management. This study demonstrates the utility of computational drug discovery in identifying plant‐derived candidates for cardiovascular and renal therapy, warranting further mechanistic validation.