Homology modeling and metabolism prediction of human carboxylesterase-2 using docking analyses by GriDock: a parallelized tool based on AutoDock 4.0.

Détails

ID Serval
serval:BIB_3CB21BB7648C
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Homology modeling and metabolism prediction of human carboxylesterase-2 using docking analyses by GriDock: a parallelized tool based on AutoDock 4.0.
Périodique
Journal of Computer-aided Molecular Design
Auteur(s)
Vistoli Giulio, Pedretti Alessandro, Mazzolari Angelica, Testa Bernard
ISSN
1573-4951[electronic], 0920-654X[linking]
Statut éditorial
Publié
Date de publication
2010
Volume
24
Numéro
9
Pages
771-787
Langue
anglais
Résumé
Metabolic problems lead to numerous failures during clinical trials, and much effort is now devoted to developing in silico models predicting metabolic stability and metabolites. Such models are well known for cytochromes P450 and some transferases, whereas less has been done to predict the activity of human hydrolases. The present study was undertaken to develop a computational approach able to predict the hydrolysis of novel esters by human carboxylesterase hCES2. The study involved first a homology modeling of the hCES2 protein based on the model of hCES1 since the two proteins share a high degree of homology (congruent with 73%). A set of 40 known substrates of hCES2 was taken from the literature; the ligands were docked in both their neutral and ionized forms using GriDock, a parallel tool based on the AutoDock4.0 engine which can perform efficient and easy virtual screening analyses of large molecular databases exploiting multi-core architectures. Useful statistical models (e.g., r (2) = 0.91 for substrates in their unprotonated state) were calculated by correlating experimental pK(m) values with distance between the carbon atom of the substrate's ester group and the hydroxy function of Ser228. Additional parameters in the equations accounted for hydrophobic and electrostatic interactions between substrates and contributing residues. The negatively charged residues in the hCES2 cavity explained the preference of the enzyme for neutral substrates and, more generally, suggested that ligands which interact too strongly by ionic bonds (e.g., ACE inhibitors) cannot be good CES2 substrates because they are trapped in the cavity in unproductive modes and behave as inhibitors. The effects of protonation on substrate recognition and the contrasting behavior of substrates and products were finally investigated by MD simulations of some CES2 complexes.
Mots-clé
affecting drug-metabolism, human liver, substrate-specificity, mammalian carboxylesterases, catalytic-properties, molecular-dynamics, small-intestine, biochemistry, hydrolysis, enzymes, Human esterases, hCES2, Prodrugs, Metabolism prediction, Parallel computing
Pubmed
Web of science
Création de la notice
01/09/2010 14:36
Dernière modification de la notice
20/08/2019 13:32
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