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

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

Type
article
Institution
UNIL/CHUV/Unisanté + institutions partenaires
Périodique
Chemistry & Biodiversity  
Auteur(s)
Vistoli, Giulio
Auteure/Auteur
Pedretti, Alessandro
Auteure/Auteur
Mazzolari, Angelica
Auteure/Auteur
Bolchi, Cristiano
Auteure/Auteur
Testa, Bernard
Auteure/Auteur
Liens vers les unités
Pharmacie  
ISSN
1612-1880[electronic]
Statut éditorial
Publié
Date de publication
2009
Volume
6
Numéro
11
Première page
2092
Dernière page/numéro d’article
2100
Langue
anglais
Résumé
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.
Sujets

Drug-Metabolism

Carboxylesterase Isoz...

Catalytic-Properties

Biochemistry

Prodrugs

Design

PID Serval
serval:BIB_8F7895F1DA48
DOI
10.1002/cbdv.200900174
PMID
19937843
WOS
000272475700030
Permalien
https://iris.unil.ch/handle/iris/226552
Date de création
2009-12-21T15:19:41.313Z
Date de création dans IRIS
2025-05-21T04:49:07Z
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