Influence of ionization state on the activation of temocapril by hCES1: a molecular-dynamics study

Chemistry & Biodiversity
Giulio VistoliBernard Testa

Abstract

Temocapril is a prodrug whose hydrolysis by carboxylesterase 1 (CES1) yields the active ACE inhibitor temocaprilat. This molecular-dynamics (MD) study uses a resolved structure of the human CES1 (hCES1) to investigate some mechanistic details of temocapril hydrolysis. The ionization constants of temocapril (pK1 and pK3) and temocaprilat (pK1, pK2, and pK3) were determined experimentally and computationally using commercial algorithms. The constants so obtained were in good agreement and revealed that temocapril exists mainly in three ionic forms (a cation, a zwitterion, and an anion), whereas temocaprilat exists in four major ionic forms (a cation, a zwitterion, an anion, and a dianion). All these ionic forms were used as ligands in 5-ns MS simulations. While the cationic and zwitterionic forms of temocapril were involved in an ion-pair bond with Glu255 suggestive of an inhibitor behavior, the anionic form remained in a productive interaction with the catalytic center. As for temocaprilat, its cation appeared trapped by Glu255, while its zwitterion and anion made a slow departure from the catalytic site and a partial egress from the protein. Only its dianion was effectively removed from the catalytic site and attracted to the p...Continue Reading

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Citations

Jun 29, 2011·Future Medicinal Chemistry·Giulio VistoliBernard Testa
Nov 26, 2013·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Kayoko OhuraTeruko Imai
Apr 9, 2011·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Takaaki Nozawa, Teruko Imai
Jan 1, 2020·Molecular Therapy. Methods & Clinical Development·Kanae KawaiHiroyuki Mizuguchi

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