Author: Lodola, Alessio ; Mulholland, Adrian J. ; Sokalski, W. Andrzej ; Langner, Karol M. ; Sirirak, Jitnapa ; Chudyk, Ewa I. ; Mor, Marco ; Dyguda-Kazimierowicz, Edyta

Fatty acid amide hydrolase (FAAH) is a member of the amidase signature family and is responsible for the hydrolytic deactivation of fatty acid amide neuromodulators, such as anandamide. FAAH carries an unusual catalytic triad consisting of Lys-Ser-Ser, which uniquely enables the enzyme to cleave amides and esters at similar rates. The acylation of 9Z-octadecenamide (oleamide, a FAAH reference substrate) has been widely investigated by computational methods, and those have shown that conformational fluctuations of the active site affect the reaction barrier. Empirical descriptors have been devised to provide a possible mechanistic explanation for such conformational effects, but a first-principles understanding is still missing. A comparison of FAAH acylation with a reference reaction in water suggests that transition-state stabilization is crucial for catalysis because the activation energy barrier falls by 6 kcal/mol in the presence of the active site. With this in mind, we have analyzed the enzymatic reaction using the differential transition-state stabilization (DTSS) approach to determine key active-site residues for lowering the barrier. We examined several QM/MM structures at the MP2 level of theory and analyzed catalytic effects with a variation-perturbation partitioning of the interaction energy into electrostatic multipole and penetration, exchange, delocalization, and correlation terms. Three residues - Thr236, Ser218, and one water molecule - appear to be essential for the stabilization of the transition state, a conclusion that is also reflected by catalytic fields and agrees with site-directed mutagenesis data. An analogous analysis for URB524, URB618, and URB694 (three potent representatives of covalent, carbamate-based FAAH inhibitors) confirms the importance of the residues involved in oleamide acylation, providing insight for future inhibitor design.

01 Apr 2009·Biochemical Society TransactionsQ2 · BIOLOGY

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

Q2 · BIOLOGY

Review

Author: Sirirak, Jitnapa ; Lodola, Alessio ; Mulholland, Adrian J. ; Mor, Marco

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.

16 Jan 2006·ChemMedChemQ3 · MEDICINE

Synthesis and Structure–Activity Relationships of FAAH Inhibitors: Cyclohexylcarbamic Acid Biphenyl Esters with Chemical Modulation at the Proximal Phenyl Ring

Q3 · MEDICINE

Article

Author: Daniele Piomelli ; Silvia Rivara ; Giuseppe Gatti ; Marco Mor ; Pier Vincenzo Plazzi ; Giovanni Piersanti ; Andrea Tontini ; Giorgio Tarzia ; Satish Kathuria ; Andrea Duranti ; Alessio Lodola

AbstractFatty acid amide hydrolase (FAAH) is a serine hydrolase that catalyzes the intracellular hydrolysis of fatty acid ethanolamides such as anandamide and oleoylethanolamide. Targeting this enzyme may have important therapeutic potentials owing to the multiple physiological roles of these amides. Cyclohexylcarbamic acid biphenyl‐3‐yl ester (URB524) was one of the most promising FAAH inhibitors so far described. We report the modulation of the electronic and steric features of the proximal phenyl ring of this compound by introducing a series of substituents at the ortho and para positions. pIC50 values were found to correlate with molecular features thought to be involved in the recognition step such as steric hindrance and hydrogen‐bonding ability. Derivatives with small polar groups at the para position of the proximal phenyl ring were slightly better FAAH inhibitors than the parent compound URB524.

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Indication	Highest Phase	Country/Location	Organization	Date
Depressive Disorder	Phase 2	IT	University of Urbino	29 May 2008
Pain	Phase 2	IT	University of Urbino	29 May 2008
Anxiety Disorders	Preclinical	IT	University of Urbino	10 May 2003

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