Hydrogen‐Bonded His93 As a Sensitive Probe for Identifying Inhibitors of the Endocannabinoid Transport Protein FABP 7

• Published in: Chemical biology & drug design 2015-05, Vol.85 (5), p.534-540
• Main Authors: Tyukhtenko, Sergiy, Chan, Karrie, Jiang, Rubin, Zhou, Han, Mercier, Richard W., Yang, De‐Ping, Makriyannis, Alexandros, Guo, Jason J.
• Format: Article
• Language: English
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/cbdd.12440

The human brain FABP ( FABP 7) 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 FABP 7 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 ( FABP 4) inhibitor BMS 309403 also binds tightly to FABP 7. Our data demonstrated that this unique His93 downfield resonance can be used as a sensitive probe for rapidly and unambiguously identifying novel high‐affinity FABP 7 ligands. The findings should help accelerate the discovery of potential drug leads for the modulation of endocannabinoid transport.