Interaction of the N-(3-Methylpyridin-2-yl)amide Derivatives of Flurbiprofen and Ibuprofen with FAAH: Enantiomeric Selectivity and Binding Mode (174 views)
Plosone (ISSN: 1932-6203linking, 1932-6203electronic), 2015 Nov 13; 10 (11 ): e0142711-N/D.
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Paper type: Journal Article , Research Support, Non-U. S. Gov'T,
Impact factor: 4.351, 5-year impact factor: 4.383
Url: Not available.
Keywords: Amidohydrolases Antagonists, Inhibitors Metabolism , Aminopyridines Chemistry , Animals , Brain Enzymology , Cyclooxygenase Inhibitors Chemistry , Drug Design , Flurbiprofen Analogs, Derivatives Chemistry , Hela Cells , Humans , Hydrolysis , Ibuprofen Analogs, Inhibitory Concentration 50 , Kinetics , Mice , Molecular Dynamics Simulation , Prostaglandin-Endoperoxide Synthases Metabolism , Protein Binding , Sprague-Dawley , Wistar , Recombinant Proteins Metabolism , Stereoisomerism,
Affiliations:
*** IBB - CNR ***
Department of Pharmacology and Clinical Neuroscience, Pharmacology Unit, Umeå University, Umeå, Sweden.
Department of Life and Environmental Sciences, Unit of Pharmaceutical, Pharmacological and Nutraceutical Sciences, University of Cagliari, via Ospedale 72, Cagliari, I-09124, Italy.
Institute of Biostructures and Bioimaging, CNR, Naples, Italy.
Departament de Fisicoquímica and Institut de Biomedicina (IBUB), Facultat de Farmàcia, Universitat de Barcelona, Santa Coloma de Gramenet, Spain.
References:
Not available.
Plosone (ISSN: 1932-6203linking, 1932-6203electronic), 2015 Nov 13; 10 (11 ): e0142711-N/D.
Export to BibTeX Export to EndNote
Paper type: Journal Article , Research Support, Non-U. S. Gov'T,
Impact factor: 4.351, 5-year impact factor: 4.383
Url: Not available.
Keywords: Amidohydrolases Antagonists, Inhibitors Metabolism , Aminopyridines Chemistry , Animals , Brain Enzymology , Cyclooxygenase Inhibitors Chemistry , Drug Design , Flurbiprofen Analogs, Derivatives Chemistry , Hela Cells , Humans , Hydrolysis , Ibuprofen Analogs, Inhibitory Concentration 50 , Kinetics , Mice , Molecular Dynamics Simulation , Prostaglandin-Endoperoxide Synthases Metabolism , Protein Binding , Sprague-Dawley , Wistar , Recombinant Proteins Metabolism , Stereoisomerism,
Affiliations:
*** IBB - CNR ***
Department of Pharmacology and Clinical Neuroscience, Pharmacology Unit, Umeå University, Umeå, Sweden.
Department of Life and Environmental Sciences, Unit of Pharmaceutical, Pharmacological and Nutraceutical Sciences, University of Cagliari, via Ospedale 72, Cagliari, I-09124, Italy.
Institute of Biostructures and Bioimaging, CNR, Naples, Italy.
Departament de Fisicoquímica and Institut de Biomedicina (IBUB), Facultat de Farmàcia, Universitat de Barcelona, Santa Coloma de Gramenet, Spain.
References:
Not available.
Interaction of the N-(3-Methylpyridin-2-yl)amide Derivatives of Flurbiprofen and Ibuprofen with FAAH: Enantiomeric Selectivity and Binding Mode
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 FAAH(T488A)-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.
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 FAAH(T488A)-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.
Interaction of the N-(3-Methylpyridin-2-yl)amide Derivatives of Flurbiprofen and Ibuprofen with FAAH: Enantiomeric Selectivity and Binding Mode
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Interaction of the N-(3-Methylpyridin-2-yl)amide Derivatives of Flurbiprofen and Ibuprofen with FAAH: Enantiomeric Selectivity and Binding Mode
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17 Records (17 excluding Abstracts).
Total impact factor: 74.831 (74.831 excluding Abstracts).
Total 5 year impact factor: 69.129 (69.129 excluding Abstracts).
Total impact factor: 74.831 (74.831 excluding Abstracts).
Total 5 year impact factor: 69.129 (69.129 excluding Abstracts).
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