Azadirachta indica

Background: Cardiovascular diseases (CVDs) remain the leading cause of mortality worldwide, with dysregulation of cholesterol metabolism as a key contributor. 3-Hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR) is the rate-limiting enzyme in cholesterol biosynthesis, targeted effectively by statins. However, statins can cause adverse effects, highlighting the need for safer, natural alternatives. Gallic acid and chlorogenic acid, abundant phenolic compounds in Azadirachta indica leaves, have shown potential HMGR inhibitory activity. The objective was to evaluate the HMGR inhibitory potential of gallic acid and chlorogenic acid through molecular docking analysis, thereby elucidating their possible role as natural lipid-lowering agents. Methods: Molecular docking was performed using AutoDock Vina across seven potential binding sites of HMGR, identified from crystal structure analysis. Ligand structures were prepared from PubChem, and receptor refinement was conducted in BIOVIA Discovery Studio. Binding affinities and ligand–protein interactions were analyzed to assess inhibitory potential. Results: Binding energies for gallic acid ranged from –3.7 to –6.0 kcal/mol, with strongest binding at Site 5 (–6.0 kcal/mol), primarily stabilized by hydrophobic (Pi–Sigma, Pi–Alkyl) and electrostatic interactions (Pi–Anion, Pi–Cation). Chlorogenic acid exhibited higher binding affinities across sites (–4.3 to –7.3 kcal/mol), with Sites 5 (–7.2 kcal/mol) and 7 (–7.3 kcal/mol) showing the strongest interactions, dominated by hydrophobic alkyl–alkyl contacts. Overall, chlorogenic acid demonstrated stronger site-specific binding than gallic acid, though both showed weaker binding compared to statins. Discussion & Conclusion: Chlorogenic acid exhibits greater affinity for HMGR than gallic acid, suggesting its potential as a moderate natural HMGR inhibitor. These findings warrant further in vitro and in vivo studies to validate their cholesterol-lowering potential and explore their use as safer alternatives or adjuncts to statin therapy.