Thermodynamics of binding of angiotensin-converting enzyme inhibitors to enzyme active site model

The density functional theory (DFT) using Becke3LYP functional and the two-layered ONIOM Becke3LYP:MNDO calculations have been carried out to investigate the structural and thermodynamic properties of 29 neutral and deprotonated angiotensin-converting enzyme inhibitors (H2O, enalaprilat, cilazaprilat, imidaprilat, perindoprilat, quinaprilat, ramiprilat, spiraprilat, trandolaprilat, fosinoprilat, omapatrilat, captopril, zofenoprilat, silanediol and keto-ACE) in complex with zinc cation and three first-shell ligands as models of active site of angiotensin-converting enzyme. The influence of deprotonation on the structure and relative energetics of model complexes was examined. Interaction enthalpies and Gibbs energies between inhibitors and angiotensin-converting enzyme active site model were calculated. The structure and thermodynamics of optimized complexes are discussed from the point of view of their biological importance. (C) 2008 Elsevier B.V. All rights reserved.