Computational Discovery of Phytochemical Modulators Targeting Hypertensive GPCRs: AT1R, ADRA1B, and ADRB1 Through Molecular Docking, Molecular Dynamics, and Network Pharmacology

Abstract

Hypertension remains a leading contributor to global cardiovascular morbidity and mortality, with G‐protein‐coupled receptors (GPCRs), including angiotensin II type 1 receptor (AT1R), α1B‐adrenergic receptor (ADRA1B), and β1‐adrenergic receptor (ADRB1), representing clinically validated therapeutic targets. This study employed an integrated computational workflow combining molecular docking, pharmacokinetic profiling, molecular dynamics (MD) simulations, MM‐GBSA binding free‐energy estimation, and network pharmacology to prioritize phytochemicals with potential modulatory activity against these receptors. A curated library of 103 phytochemicals was screened and benchmarked against reference antihypertensive drugs (losartan, prazosin, and metoprolol). Sequential prioritization based on docking performance, drug‐likeness (including Lipinski's and Veber's criteria), toxicity prediction, and cytochrome P450 (CYP) interaction profiles identified α‐amyrin and taraxerol as lead candidates. Docking analyses predicted favorable binding poses within the receptor‐binding regions, while 50 ns MD simulations indicated sustained receptor–ligand stability under the simulated conditions. Root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (rGyr), solvent‐accessible surface area (SASA), protein–ligand interaction persistence, and MM‐GBSA analyses collectively supported stable complex formation comparable to the reference compounds. Network pharmacology predicted enrichment of MAPK‐, inflammatory‐, and cAMP‐associated signaling pathways relevant to hypertension. Collectively, these computational findings identify pentacyclic triterpenoids, particularly α‐amyrin and taraxerol, as promising scaffolds for further experimental validation as potential modulators of hypertension‐related GPCRs.