Exploring <i>Artocarpus heterophyllus</i> phytochemicals as novel mineralocorticoid receptor inhibitors: A computational approach to hypertension therapy

This research intends to explore the potential of phytochemicals derived from Artocarpus heterophyllus (jackfruit) as novel mineralocorticoid receptor (MR) inhibitors for hypertension therapy. The primary objective is to identify natural compounds with superior binding affinities and stability compared to the native ligand. This offers a safer alternative to synthetic antihypertensive drugs, which often cause adverse effects. A computational approach was employed, combining molecular docking, molecular dynamics simulations (MDS), and absorption, digestion, metabolism, excretion, and toxicity (ADMET) analysis. A database of 60 phytochemicals from A. heterophyllus was prepared, and their binding affinities to the MR protein (PDB ID: 5L7E) were evaluated using the DockThor platform. The top six ligands with the highest binding affinities were further analyzed through 200-ns MDS to assess structural and thermodynamic stability. Key descriptors such as radius of gyration (R g ), root mean square fluctuation (RMSF), root mean square deviation (RMSD), solvent-accessible surface area (SASA), and binding free energy change (ΔG) were calculated to evaluate the stability and interactions of the protein-ligand complexes. Six phytochemicals exhibited stronger binding affinities than the native ligand (-9.619 kcal/mol), with heterophylol (ligand01) showing the highest binding affinity (-10.378 kcal/mol). MDS revealed that heterophylol and artoindonesianin Q (ligand02) formed the most stable complexes, with heterophylol demonstrating the lowest binding free energy changes (ΔG = -39.91 kcal/mol). Structural analyses confirmed the stability of these complexes over time, with minimal fluctuations in RMSD, RMSF, and R g . Hydrogen bond interactions with key residues (e.g., CYS849, ARG817) and hydrophobic interactions (e.g., LEU766, MET852) further validated these ligands’ stability and binding efficacy. The findings highlight the potential of A. heterophyllus phytochemicals, particularly heterophylol and artoindonesianin Q, as natural MR inhibitors for hypertension treatment. These compounds demonstrated superior binding affinities, structural stability, and thermodynamic favorability compared to the native ligand, positioning them as promising candidates for further experimental and clinical validation. This study provides a computational foundation for developing safer, plant-based antihypertensive therapies, contributing to the advancement of natural product-based drug discovery.