English   español  
Please use this identifier to cite or link to this item: http://hdl.handle.net/10261/31137
Share/Impact:
Statistics
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:

Title

Reactivity versus steric effects in fluorinated ketones as esterase inhibitors: a quantum mechanical and molecular dynamics study

AuthorsRayo, Josep; Muñoz, Lourdes ; Rosell, Gloria ; Hammock, Bruce D.; Guerrero, Ángel ; Luque, F. Javier; Pouplana, Ramón
KeywordsFluorinated ketones
Esterase
Quantum mechanical computations
Molecular dynamics
Structure-based drug design
Issue Date31-Jul-2010
PublisherSpringer
CitationJournal of Molecular Modeling 16(11): 1753-1764 (2010)
AbstractCarboxylesterases (CEs) are a family of ubiquitous enzymes with broad substrate specificity, and their inhibition may have important implications in pharmaceutical and agrochemical fields. One of the most potent inhibitors both for mammalian and insect CEs are trifluoromethyl ketones (TFMKs), but the mechanism of action of these chemicals is not completely understood. This study examines the balance between reactivity versus steric effects in modulating the activity against human carboxylesterase 1. The intrinsic reactivity of the ketone moiety is determined from quantum mechanical computations, which combine gas phase B3LYP calculations with hydration free energies estimated with the IEF/MST model. In addition, docking and molecular dynamics simulations are used to explore the binding mode of the inhibitors along the deep gorge that delineates the binding site. The results point out that the activity largely depends on the nature of the fluorinated ketone, since the activity is modulated by the balance between the intrinsic electrophilicity of the carbonyl carbon atom and the ratio between keto and hydrate forms. However, the results also suggest that the correct alignment of the alkyl chain in the binding site can exert a large influence on the inhibitory activity, as this effect seems to override the intrinsic reactivity features of the fluorinated ketone. Overall, the results sustain a subtle balance between reactivity and steric effects in modulating the inhibitory activity of TFMK inhibitors.
Description12 pages, 10 figures, 3 tables.-- PMID: 20676708 [Pubmed].-- PMCID: PMC3014912.-- NIHMSID: NIHMS250369.-- Printed version published Nov 2010.
Publisher version (URL)http://dx.doi.org/10.1007/s00894-010-0807-4
URIhttp://hdl.handle.net/10261/31137
DOI10.1007/s00894-010-0807-4
ISSN1610-2940
E-ISSN0948-5023
Appears in Collections:(IQAC) Artículos
Files in This Item:
File Description SizeFormat 
Rayo_Josep_et_al.pdfArticle1,26 MBAdobe PDFThumbnail
View/Open
Rayo_Josep_et_al_2.pdfSupporting Information211,59 kBAdobe PDFThumbnail
View/Open
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.