Insights into the mechanism and inhibition of fatty acid amide hydrolase from quantum mechanics/molecular mechanics (QM/MM) modelling

2009 ◽  
Vol 37 (2) ◽  
pp. 363-367 ◽  
Author(s):  
Alessio Lodola ◽  
Marco Mor ◽  
Jitnapa Sirirak ◽  
Adrian J. Mulholland
Keyword(s):  
Quantum Mechanics ◽  
Fatty Acid ◽  
Molecular Mechanics ◽  
Fatty Acid Amide Hydrolase ◽  
Acid Amide ◽  
Catalytic Triad ◽  
Molecular Mechanics Calculations ◽  
Covalent Inhibitors ◽  
Amide Hydrolase ◽  
Fatty Acid Amide

FAAH (fatty acid amide hydrolase) is a promising target for the treatment of several central nervous system and peripheral disorders. Combined QM/MM (quantum mechanics/molecular mechanics) calculations have elucidated the role of its unusual catalytic triad in the hydrolysis of oleamide and oleoylmethyl ester substrates, and have identified the productive inhibitor-binding orientation for the carbamoylating compound URB524. These are potentially crucial insights for designing new covalent inhibitors of this drug target.

scholarly journals Covalent Inhibitors of Fatty Acid Amide Hydrolase: A Rationale for the Activity of Piperidine and Piperazine Aryl Ureas

2011 ◽  
Vol 54 (19) ◽  
pp. 6612-6623 ◽  
Author(s):  
Giulia Palermo ◽  
Davide Branduardi ◽  
Matteo Masetti ◽  
Alessio Lodola ◽  
Marco Mor ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Amide Hydrolase ◽  
Acid Amide ◽  
Covalent Inhibitors ◽  
Amide Hydrolase ◽  
Fatty Acid Amide

Fatty acid amide hydrolase inhibitors display broad selectivity and inhibit multiple carboxylesterases as off-targets

2007 ◽  
Vol 52 (4) ◽  
pp. 1095-1105 ◽  
Author(s):  
Di Zhang ◽  
Anita Saraf ◽  
Teodozyi Kolasa ◽  
Pramila Bhatia ◽  
Guo Zhu Zheng ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Amide Hydrolase ◽  
Acid Amide ◽  
Amide Hydrolase ◽  
Fatty Acid Amide

Exacerbation of Background Nuclear Cataracts in Sprague-Dawley Rats in Embryo-Fetal Development Studies With JNJ-42165279, a Fatty Acid Amide Hydrolase Inhibitor

2021 ◽  
pp. 019262332110104
Author(s):  
Marjolein van Heerden ◽  
Wendy Roosen ◽  
Sophie Lachau-Durand ◽  
Graham Bailey ◽  
Anthony Ndifor
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Amide Hydrolase ◽  
Acid Amide ◽  
In Utero ◽  
Histological Evaluation ◽  
High Dose ◽  
Lens Fiber ◽  
Sprague Dawley ◽  
Amide Hydrolase ◽  
Fatty Acid Amide

Fetal examinations in embryo-fetal developmental (EFD) studies are based on macroscopic and dissecting microscopic evaluations, and histopathology is rarely performed other than to confirm macroscopic findings. Fetal lens examination is therefore generally limited to the presence, size, shape, and color of any abnormality. In a Sprague-Dawley rat EFD study with the fatty acid amide hydrolase (FAAH) inhibitor JNJ-42165279, an unusually high incidence of macroscopic granular foci was noted within the lens of gestation day 21 fetuses across all groups including controls, with higher incidence in the high-dose group. On histological evaluation of the lenses from fetuses with/without gross findings, primary lens fiber hypertrophy (swelling) and degeneration were observed across vehicle- and JNJ-42165279-exposed fetuses. In a follow-up study to investigate the progression or resolution of the fetal lens changes, animals exposed to suprapharmacological doses of JNJ-42165279 in utero had higher incidence of nuclear cataracts as detected via slit-lamp ophthalmic examinations on postnatal days 18 to 21 and 35 to 41. No histologic correlates for these cataracts were identified. We conclude that fetal primary lens fiber hypertrophy and nuclear cataracts at ophthalmology, are common background changes in this rat strain that are exacerbated by in utero exposure to the FAAH inhibitor JNJ-42165279.

Sign in / Sign up

Export Citation Format

Share Document