Theoretical Study of Gas-Phase Acidities of Selected Angiotensin-Converting Enzyme Inhibitors

Abstract

The structure and gas-phase acidities of six members of large angiotensin-converting enzyme (ACE) inhibitor family [cilazaprilat, silanediol, fosinoprilat, AcSDKP, angiotensin I (terminal part), and RXP 407] have been studied using the ONIOM Becke3LYP/6-311+G(d,p):HF/3-21G * method. The investigated ACE inhibitors are weak acids with calculated acidity of about 1270-1650 kJ mol −1 . Of acids studied the highest gas-phase acidity (1273 kJ mol −1 ) possesses experimental ACE inhibitor RXP 407. This drug, according to the computed pK a value (3.2), is also in water solution the most acidic compound of the ACE inhibitors investigated.

Interplay of thermochemistry and Structural Chemistry, the journal (volume 16, 2005) and the discipline

“…Then, Šramko et al [120] report the results of their theoretical study using DFT method on the structure and gas-phase acidities of six members of large angiotensinconverting enzyme (ACE) inhibitor family. Macroscopic dissociation constants were calculated using web-based tool SPARC.…”

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

“…The structures of the complexes were modeled based on available structural information [1,[8][9][10] taken from crystallographic structures found in Brookhaven protein database [46] and our previous results [7,14,47,48]. All ACE inhibitors were studied in the biologically active deesterified form.…”

“…This explains why N-terminal functional group of studied inhibitors was examined in its ionized and also nonionized form. It is well known [7,12,48,49], that the N-terminal carboxyl group of dicarboxyl-containing ACE inhibitors is more acidic than the C-terminal carboxyl group, what is the reason why C-terminal carboxyl group was studied in its nonionized form.…”

“…It has been shown [7,48,[60][61][62][63][64] that the integrated MO approach, ONIOM, provides an ideal method for the accurate calculations of large systems. For such molecules, accurate calculations are often too expensive and out of reach.…”

“…However, the deprotonation reactions of ACE inhibitors in complex with the enzyme active site have not yet been intensively investigated neither experimentally nor theoretically. The gas-phase acidities and aqueous proton dissociation constants (pK a values) of some ACE inhibitors have been determined theoretically in our previous works [7,12,48]. The calculated gas-phase acidities of isolated and complexed ACE inhibitors at 298 K are summarized in Table 3.…”