Please use this identifier to cite or link to this item: http://hdl.handle.net/2445/107153
Title: Interaction of the N-(3-Methylpyridin-2-yl)amide Derivatives of Flurbiprofen and Ibuprofen with FAAH: Enantiomeric Selectivity and Binding Mode
Author: Karlsson, Jessica
Morgillo, Carmine M
Deplano, Alessandro
Smaldone, Giovanni
Pedone, Emilia
Luque Garriga, F. Xavier
Svensson, Mona
Novellino, Ettore
Congiu, Cenzo
Onnis, Valentina
Catalanotti, Bruno
Fowler, Christopher J.
Keywords: Grip
Enantiòmers
Prostaglandines
Influenza
Enantiomers
Prostaglandins
Issue Date: 13-Nov-2015
Publisher: Public Library of Science (PLoS)
Abstract: Background Combined fatty acid amide hydrolase (FAAH) and cyclooxygenase (COX) inhibition is a promising approach for pain-relief. The Flu-AM1 and Ibu-AM5 derivatives of flurbiprofen and ibuprofen retain similar COX-inhibitory properties and are more potent inhibitors of FAAH than the parent compounds. However, little is known as to the nature of their interaction with FAAH, or to the importance of their chirality. This has been explored here. Methodology/Principal Findings FAAH inhibitory activity was measured in rat brain homogenates and in lysates expressing either wild-type or FAAHT488A-mutated enzyme. Molecular modelling was undertaken using both docking and molecular dynamics. The (R)- and (S)-enantiomers of Flu-AM1 inhibited rat FAAH with similar potencies (IC50 values of 0.74 and 0.99 μM, respectively), whereas the (S)-enantiomer of Ibu-AM5 (IC50 0.59 μM) was more potent than the (R)-enantiomer (IC50 5.7 μM). Multiple inhibition experiments indicated that both (R)-Flu-AM1 and (S)-Ibu-AM5 inhibited FAAH in a manner mutually exclusive to carprofen. Computational studies indicated that the binding site for the Flu-AM1 and Ibu-AM5 enantiomers was located between the acyl chain binding channel and the membrane access channel, in a site overlapping the carprofen binding site, and showed a binding mode in line with that proposed for carprofen and other non-covalent ligands. The potency of (R)-Flu-AM1 was lower towards lysates expressing FAAH mutated at the proposed carprofen binding area than in lysates expressing wild-type FAAH. Conclusions/Significance The study provides kinetic and structural evidence that the enantiomers of Flu-AM1 and Ibu-AM5 bind in the substrate channel of FAAH. This information will be useful in aiding the design of novel dual-action FAAH: COX inhibitors.
Note: Reproducció del document publicat a: https://doi.org/10.1371/journal.pone.0142711
It is part of: PLoS One, 2015, vol. 10, num. 11, p. e0142711
Related resource: https://doi.org/10.1371/journal.pone.0142711
URI: http://hdl.handle.net/2445/107153
ISSN: 1932-6203
Appears in Collections:Articles publicats en revistes (Nutrició, Ciències de l'Alimentació i Gastronomia)
Articles publicats en revistes (Institut de Biomedicina (IBUB))

Files in This Item:
File Description SizeFormat 
656637.pdf1.89 MBAdobe PDFView/Open


This item is licensed under a Creative Commons License Creative Commons