title: Hydrogen-bonded His93 as a sensitive probe for identifying inhibitors of the endocannabinoid transport protein FABP7.
abstract: The human brain FABP (FABP7) has been shown to be an intracellular carrier protein that can significantly potentiate the uptake of the endocannabinoid anandamide. For this reason, there is a great interest in the discovery and development of FABP7 inhibitors for treating stress, pain, inflammation, and drug abuse. We found that in the (1) H-NMR spectrum of the protein, a well-separated downfield resonance arising from the hydrogen-bonded His93 side chain is very sensitive to ligand binding. Using this characteristic spectral marker together with another well-resolved upfield resonance from the side chain of Val84, we have identified that an adipocyte FABP (FABP4) inhibitor BMS309403 also binds tightly to FABP7. Our data demonstrated that this unique His93 downfield resonance can be used as a sensitive probe for rapidly and unambiguously identifying novel high-affinity FABP7 ligands. The findings should help accelerate the discovery of potential drug leads for the modulation of endocannabinoid transport.
authors.affiliation: Center for Drug Discovery, Department of Pharmaceutical Sciences and Department of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Avenue, Boston, MA, 02115, USA.
authors.forename: Sergiy
authors.initials: S
authors.lastname: Tyukhtenko
authors.forename: Karrie
authors.initials: K
authors.lastname: Chan
authors.forename: Rubin
authors.initials: R
authors.lastname: Jiang
authors.forename: Han
authors.initials: H
authors.lastname: Zhou
authors.forename: Richard W
authors.initials: RW
authors.lastname: Mercier
authors.forename: De-Ping
authors.initials: DP
authors.lastname: Yang
authors.forename: Alexandros
authors.initials: A
authors.lastname: Makriyannis
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Guo
mesh_terms: D001713:Biphenyl Compounds / Q000737:chemistry / Q000378:metabolism; D002186:Cannabinoids / Q000737:chemistry / Q000378:metabolism; D050556:Fatty Acid-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006639:Histidine / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D011720:Pyrazoles / Q000737:chemistry / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000302:isolation & purification
chemical_list: C559288:2-(2'-(5-ethyl-3,4-diphenyl-1H-pyrazol-1-yl)biphenyl-3-yloxy)acetic acid; D001713:Biphenyl Compounds; D002186:Cannabinoids; C493410:FABP4 protein, human; D050556:Fatty Acid-Binding Proteins; D008024:Ligands; D011720:Pyrazoles; D011994:Recombinant Proteins; D006639:Histidine
keywords: NMR; anandamide transport; endocannabinoids; fatty acid binding protein