title: In silico prediction of human carboxylesterase-1 (hCES1) metabolism combining docking analyses and MD simulations.
abstract: Metabolic problems lead to numerous failures during clinical trials, and much effort is now devoted in developing in silico models predicting metabolic stability and metabolites. Such models are well known for cytochromes P450 and some transferases, whereas little has been done to predict the hydrolytic 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 hCES1. The study involves both docking analyses of known substrates to develop predictive models, and molecular dynamics (MD) simulations to reveal the in situ behavior of substrates and products, with particular attention being paid to the influence of their ionization state. The results emphasize some crucial properties of the hCES1 catalytic cavity, confirming that as a trend with several exceptions, hCES1 prefers substrates with relatively smaller and somewhat polar alkyl/aryl groups and larger hydrophobic acyl moieties. The docking results underline the usefulness of the hydrophobic interaction score proposed here, which allows a robust prediction of hCES1 catalysis, while the MD simulations show the different behavior of substrates and products in the enzyme cavity, suggesting in particular that basic substrates interact with the enzyme in their unprotonated form.
authors.affiliation: Dipartimento di Scienze Farmaceutiche Pietro Pratesi, Facoltà di Farmacia, Università degli Studi di Milano, Via Mangiagalli 25, I-20133 Milano, Italy. giulio.vistoli@unimi.it
authors.forename: Giulio
authors.initials: G
authors.lastname: Vistoli
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pedretti
authors.forename: Angelica
authors.initials: A
authors.lastname: Mazzolari
authors.forename: Bernard
authors.initials: B
authors.lastname: Testa
mesh_terms: D002265:Carboxylic Ester Hydrolases / Q000737:chemistry* / Q000378:metabolism*; D020134:Catalytic Domain; D003198:Computer Simulation; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D013379:Substrate Specificity
chemical_list: D002265:Carboxylic Ester Hydrolases; C474609:CES1 protein, human