TOPIC: Integrated In Silico Discovery of Novel Angiotensin-Converting Enzyme Inhibitors from Allium cepa Phytoconstituents: Molecular Docking, ADMET Profiling, Molecular Dynamics, and MMGBSA Studies

Hypertension remains a major global public health issue and is highly linked with cardiovascular complications and premature mortality. Although angiotensin-converting enzyme (ACE) inhibitors are widely used in the management of hypertension, their chronic use is often accompanied by devastating side effects, highlighting the need for safer and cheaper alternatives from medicinal plants. This study investigated the inhibitory potential of phytochemicals from Allium cepa against ACE using an integrated computational workflow involving molecular docking, drug-likeness and ADMET assessment, molecular dynamics simulation, and molecular mechanics generalized Born surface area (MMGBSA). Sixty phytochemicals were retrieved from Dr. Duke’s phytochemical database and screened against ACE (PDB ID: 1O86). Molecular docking analysis identified 31 phytoconstituents with better predicted scores than the reference drug, lisinopril. Among the compounds, stigmasterol (-9.9 kcal/mol), quercetin (-8.4 kcal/mol), isorhamnetin (-8.3 kcal/mol), and kaempferol (-8.2 kcal/mol) exhibited favorable interactions with essential amino acid residues within the ACE binding pocket through hydrogen bonding and hydrophobic interactions. Drug-likeness and pharmacokinetic evaluation predicted acceptable pharmacokinetic features and minimal toxicity for the prioritized compounds. Molecular dynamics simulations further suggested stable interactions between ligand–protein complexes throughout the 100 ns simulation period, with RMSD values remaining within acceptable limits. MMGBSA analysis showed that stigmasterol exhibited the most favorable predicted binding free energy among the phytochemicals investigated. Collectively, these computational outcomes identify several phytoconstituents in Allium cepa as promising bioactive compounds for further investigation as possible ACE inhibitors. However, further experimental validation via in vitro and in vivo assessment is needed to establish their therapeutic potential and safety.