Molecular Docking and Optimization of ACE Inhibitors Derived from Captopril

Angiotensin-converting enzyme (ACE) plays a pivotal role in the regulation of blood pressure through the renin–angiotensin system, making it a prime therapeutic target for hypertension and related cardiovascular disorders. Captopril, the first clinically approved ACE inhibitor, has served as a structural template for the design of novel analogues with improved potency and pharmacokinetic properties. In this study, molecular docking techniques were employed to investigate the binding interactions of captopril-derived analogues with the active site of ACE. Structural modifications were introduced to optimize hydrogen bonding, hydrophobic contacts, and metal ion coordination within the catalytic pocket. Docking simulations revealed that several derivatives exhibited enhanced binding affinities compared to captopril, particularly through improved interactions with the zinc ion and key residues such as His383, His387, and Glu411. Optimization strategies focused on substituent variation at the thiol and proline moieties, leading to analogues with superior predicted inhibitory activity. These findings highlight the potential of rational drug design and computational approaches in developing next-generation ACE inhibitors with improved efficacy and reduced side effects.