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

Details

Serval ID
serval:BIB_8F7895F1DA48
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Influence of ionization state on the activation of temocapril by hCES1: a molecular-dynamics study.
Journal
Chemistry & Biodiversity
Author(s)
Vistoli Giulio, Pedretti Alessandro, Mazzolari Angelica, Bolchi Cristiano, Testa Bernard
ISSN
1612-1880[electronic]
Publication state
Published
Issued date
2009
Volume
6
Number
11
Pages
2092-2100
Language
english
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 protein surface by Lys residues. A detailed mechanism of product egress emerges from the simulations.
Keywords
Drug-Metabolism, Carboxylesterase Isozymes, Catalytic-Properties, Biochemistry, Prodrugs, Design
Pubmed
Web of science
Create date
21/12/2009 16:19
Last modification date
20/08/2019 14:53
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