English   español  
Please use this identifier to cite or link to this item: http://hdl.handle.net/10261/48045
logo share SHARE logo core CORE   Add this article to your Mendeley library MendeleyBASE

Visualizar otros formatos: MARC | Dublin Core | RDF | ORE | MODS | METS | DIDL
Exportar a otros formatos:


Computational Prediction of Structure−Activity Relationships for the Binding of Aminocyclitols to β-Glucocerebrosidase

AuthorsDíaz, Lucía; Bujons Vilàs, Jordi ; Delgado, Antonio; Gutiérrez-de-Terán, Hugo; Åqvist, Johan
Issue Date2011
PublisherAmerican Chemical Society
CitationJournal of Chemical Information and Modeling
AbstractGlucocerebrosidase (GCase, acid β-Glucosidase) hydrolyzes the sphingolipid glucosylceramide into glucose and ceramide. Mutations in this enzyme lead to a lipid metabolism disorder known as Gaucher disease. The design of competitive inhibitors of GCase is a promising field of research for the design of pharmacological chaperones as new therapeutic agents. Using a series of recently reported molecules with experimental binding affinities for GCase in the nanomolar to micromolar range, we here report an extensive theoretical analysis of their binding mode. On the basis of molecular docking, molecular dynamics, and binding free energy calculations using the linear interaction energy method (LIE), we provide details on the molecular interactions supporting ligand binding in the different families of compounds. The applicability of other computational approaches, such as the COMBINE methodology, is also investigated. The results show the robustness of the standard parametrization of the LIE method, which reproduces the experimental affinities with a mean unsigned error of 0.7 kcal/mol. Several structure−activity relationships are established using the computational models here provided, including the identification of hot spot residues in the binding site. The models derived are envisaged as important tools in ligand-design programs for GCase inhibitors.
Publisher version (URL)http://dx.doi.org/10.1021/ci100453a
Appears in Collections:(IQAC) Artículos
Files in This Item:
There are no files associated with this item.
Show full item record
Review this work

Related articles:

WARNING: Items in Digital.CSIC are protected by copyright, with all rights reserved, unless otherwise indicated.