Interaction of the N-(3-Methylpyridin-2-yl)amide Derivatives of Flurbiprofen and Ibuprofen with FAAH: Enantiomeric Selectivity and Binding Mode.
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...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2015-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4643906?pdf=render |
| _version_ | 1818032607620759552 |
|---|---|
| author | Jessica Karlsson Carmine M Morgillo Alessandro Deplano Giovanni Smaldone Emilia Pedone F Javier Luque Mona Svensson Ettore Novellino Cenzo Congiu Valentina Onnis Bruno Catalanotti Christopher J Fowler |
| author_facet | Jessica Karlsson Carmine M Morgillo Alessandro Deplano Giovanni Smaldone Emilia Pedone F Javier Luque Mona Svensson Ettore Novellino Cenzo Congiu Valentina Onnis Bruno Catalanotti Christopher J Fowler |
| author_sort | Jessica Karlsson |
| collection | DOAJ |
| description | 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.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.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. |
| first_indexed | 2024-12-10T06:10:04Z |
| format | Article |
| id | doaj.art-7c0231800b9a4742aa904b05b0831370 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-10T06:10:04Z |
| publishDate | 2015-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-7c0231800b9a4742aa904b05b08313702022-12-22T01:59:35ZengPublic Library of Science (PLoS)PLoS ONE1932-62032015-01-011011e014271110.1371/journal.pone.0142711Interaction of the N-(3-Methylpyridin-2-yl)amide Derivatives of Flurbiprofen and Ibuprofen with FAAH: Enantiomeric Selectivity and Binding Mode.Jessica KarlssonCarmine M MorgilloAlessandro DeplanoGiovanni SmaldoneEmilia PedoneF Javier LuqueMona SvenssonEttore NovellinoCenzo CongiuValentina OnnisBruno CatalanottiChristopher J FowlerCombined 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.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.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.http://europepmc.org/articles/PMC4643906?pdf=render |
| spellingShingle | Jessica Karlsson Carmine M Morgillo Alessandro Deplano Giovanni Smaldone Emilia Pedone F Javier Luque Mona Svensson Ettore Novellino Cenzo Congiu Valentina Onnis Bruno Catalanotti Christopher J Fowler Interaction of the N-(3-Methylpyridin-2-yl)amide Derivatives of Flurbiprofen and Ibuprofen with FAAH: Enantiomeric Selectivity and Binding Mode. PLoS ONE |
| title | Interaction of the N-(3-Methylpyridin-2-yl)amide Derivatives of Flurbiprofen and Ibuprofen with FAAH: Enantiomeric Selectivity and Binding Mode. |
| title_full | Interaction of the N-(3-Methylpyridin-2-yl)amide Derivatives of Flurbiprofen and Ibuprofen with FAAH: Enantiomeric Selectivity and Binding Mode. |
| title_fullStr | Interaction of the N-(3-Methylpyridin-2-yl)amide Derivatives of Flurbiprofen and Ibuprofen with FAAH: Enantiomeric Selectivity and Binding Mode. |
| title_full_unstemmed | Interaction of the N-(3-Methylpyridin-2-yl)amide Derivatives of Flurbiprofen and Ibuprofen with FAAH: Enantiomeric Selectivity and Binding Mode. |
| title_short | Interaction of the N-(3-Methylpyridin-2-yl)amide Derivatives of Flurbiprofen and Ibuprofen with FAAH: Enantiomeric Selectivity and Binding Mode. |
| title_sort | interaction of the n 3 methylpyridin 2 yl amide derivatives of flurbiprofen and ibuprofen with faah enantiomeric selectivity and binding mode |
| url | http://europepmc.org/articles/PMC4643906?pdf=render |
| work_keys_str_mv | AT jessicakarlsson interactionofthen3methylpyridin2ylamidederivativesofflurbiprofenandibuprofenwithfaahenantiomericselectivityandbindingmode AT carminemmorgillo interactionofthen3methylpyridin2ylamidederivativesofflurbiprofenandibuprofenwithfaahenantiomericselectivityandbindingmode AT alessandrodeplano interactionofthen3methylpyridin2ylamidederivativesofflurbiprofenandibuprofenwithfaahenantiomericselectivityandbindingmode AT giovannismaldone interactionofthen3methylpyridin2ylamidederivativesofflurbiprofenandibuprofenwithfaahenantiomericselectivityandbindingmode AT emiliapedone interactionofthen3methylpyridin2ylamidederivativesofflurbiprofenandibuprofenwithfaahenantiomericselectivityandbindingmode AT fjavierluque interactionofthen3methylpyridin2ylamidederivativesofflurbiprofenandibuprofenwithfaahenantiomericselectivityandbindingmode AT monasvensson interactionofthen3methylpyridin2ylamidederivativesofflurbiprofenandibuprofenwithfaahenantiomericselectivityandbindingmode AT ettorenovellino interactionofthen3methylpyridin2ylamidederivativesofflurbiprofenandibuprofenwithfaahenantiomericselectivityandbindingmode AT cenzocongiu interactionofthen3methylpyridin2ylamidederivativesofflurbiprofenandibuprofenwithfaahenantiomericselectivityandbindingmode AT valentinaonnis interactionofthen3methylpyridin2ylamidederivativesofflurbiprofenandibuprofenwithfaahenantiomericselectivityandbindingmode AT brunocatalanotti interactionofthen3methylpyridin2ylamidederivativesofflurbiprofenandibuprofenwithfaahenantiomericselectivityandbindingmode AT christopherjfowler interactionofthen3methylpyridin2ylamidederivativesofflurbiprofenandibuprofenwithfaahenantiomericselectivityandbindingmode |