In Silico Docking, ADMET, and Density-Functional Profiling of Allium sativum Organosulfur Compounds as Candidate Angiotensin-Converting Enzyme Inhibitors

Abstract

Background: Hypertension is a leading and rising contributor to cardiovascular morbidity and mortality in India, and dietary garlic (Allium sativum) has long been associated with modest blood-pressure benefits. Angiotensin-converting enzyme (ACE) is a central therapeutic target in hypertension. We computationally prioritized selected A. sativum organosulfur constituents as candidate ACE inhibitors. Methods: Twelve organosulfur compounds reported from garlic, together with the reference ACE inhibitor captopril, were subjected to an integrated in silico workflow comprising molecular docking against human ACE (five poses per ligand), interaction profiling, drug-likeness and ADMET prediction, density-functional theory (DFT) reactivity descriptors, and 100-ns molecular-dynamics (MD) prioritization with MM-GBSA free-energy estimation for the three highest-priority candidates. Compounds were ranked using an integrated docking-ADMET-DFT scheme. Results: Best docking energies for the garlic compounds ranged from -5.83 to -7.94 kcal/mol, versus -8.57 kcal/mol for captopril. Gamma-glutamyl-S-allyl cysteine (-7.94 kcal/mol), ajoene (-7.87 kcal/mol) and S-allyl mercaptocysteine (-7.34 kcal/mol) were the top-ranked garlic candidates, engaging conserved ACE active-site residues (His383, His387, His513, Glu411, Tyr523, Lys511, Phe457). All compounds showed zero Lipinski violations, and most exhibited high predicted gastrointestinal absorption. DFT HOMO-LUMO gaps spanned 3.09-4.69 eV. Over 100-ns MD the three prioritized complexes remained stable (protein RMSD 2.02-2.35 Angstrom) with favourable MM-GBSA free energies (-35.66 to -48.46 kcal/mol). Conclusion: Several garlic organosulfur compounds, led by gamma-glutamyl-S-allyl cysteine, ajoene and S-allyl mercaptocysteine, show promising in silico ACE-binding and acceptable drug-likeness, providing a rational, hypothesis-generating shortlist for biochemical ACE-inhibition validation.