Exploring the influence of Cu(II), Fe(III), Sn(II), and Ni(II) complexes of captopril drug for improved antihypertensive activity: A DFT, molecular docking, and MD simulation study

Captopril (CAP), one of the common angiotensin-converting enzyme (ACE) inhibitors, is disadvantaged by its oxidative instability and changing bioavailability. To improve its pharmacological performance, complexes of CAP with Cu(II), Ni(II), Fe(III), and Sn(II) were synthesized and investigated by element analysis, spectroscopic, and thermal analyses, which confirmed bidentate coordination of thiol sulfur and carbonyl oxygen atoms of thiol groups of the drug molecule. Density functional theory (DFT) and molecular docking studies indicated that the coordination of metal significantly changed electronic properties, as well as binding affinities of the drug molecule. Out of those analyzed complexes, Cu(II)CAP possessed the minimum highest occupied molecular orbital (HOMO) - lowest unoccupied molecular orbital (LUMO) gap value (3.25 eV) and the highest ACE binding energy (-10.6 kcal/mol). Moreover, molecular dynamics studies verified its structural integrity, increased hydrogen bonding, and a more rigid protein–ligand structure compared to native CAP. These outcomes suggest that coordination of Cu(II) improves both physicochemical and biological properties of CAP, indicating a potential route for designing better ACE inhibitors.