Computation drug design for ACE inhibitor for high blood pressure management and assessment of pharmacokinetics and toxicity of promising compounds isolated from Gymnema sylvestre

This study employs computational drug design approaches to identify and optimize ACE inhibitors from G. sylvestre's isolated compounds, assessing their pharmacokinetic and toxicity profiles. The receptor (PDB: 1o86) was retrieved from RCSB, prepared, and analyzed for active binding sites. Ligands were prepared and docked using AutoDock. Results were analyzed, visualized, and further evaluated through MD simulations, pharmacokinetics analysis, and toxicity. The molecular docking analysis of 12 compounds isolated from G. sylvestre revealed that oleanolic acid (7), β-amyrine (6), and betulinic acid (9) exhibited the strongest binding affinities to ACE, with binding energies of −10.2, −9.1, and − 9.0 kcal/mol, respectively. Furthermore, MDS confirmed the stability and specificity of these compounds. Additionally, oleanolic acid (7) exhibits a promising pharmacokinetic profile and relatively low toxicity, as indicated by its high intraperitoneal LD50 value, suggesting its potential as a safe and effective compound for food formulation and hypertension management. The acute toxicity predictions for 20S-hydroxy-4,6,24(28)-ergostatrien-3-one (3), β-amyrine (6), oleanolic acid (7), and betulinic acid (9) show promising results, particularly for intraperitoneal and oral administration. 20S-hydroxy-4,6,24(28)-ergostatrien-3-one (3) has an intraperitoneal LD50 of 928,700 mg/kg and oral LD50 of 1,679,000 mg/kg, while β-amyrine (6) and oleanolic acid (7) exhibit even higher intraperitoneal LD50 values of 1749,000 mg/kg, indicating low toxicity and suggesting these compounds are relatively safe for use via these routes. Computational drug design and pharmacokinetic/toxicity evaluation identified G. sylvestre-derived oleanolic acid (7) and β-amyrine (6) as promising ACE-inhibitors for hypertension management. These natural compounds exhibit potential for improved safety and efficacy profiles compared to existing synthetic ACE inhibitors.