QM/MM modelling of oleamide hydrolysis in fatty acid amide hydrolase (FAAH) reveals a new mechanism of nucleophile activation

Lodola, Alessio; Mor, Marco; Hermann, Johannes C.; Tarzia, Giorgio; Piomelli, Daniele; Mulholland, Adrian J.

doi:10.1039/b503887a

Cited by 65 publications

(117 citation statements)

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“…This QM/MM method has previously been validated for FAAH. [4][5][6] The calculations clearly show that the carbamoylation in orientation II is energetically preferred, thus identifying II as the productive binding mode. This provides a theoretical basis for SAR interpretation of URB524 analogues.…”

Section: 11mentioning

confidence: 95%

“…The resulting structures were solvated by a 25 Å radius sphere of TIP3P water molecules and equilibrated by 130 ps of molecular dynamics (MD), similar to the procedure reported in ref. 4, and described in the electronic supplementary information (ESI{). The complexes were then minimized to an energy gradient of 0.01 kcal mol 21 Å…”

Section: 11mentioning

confidence: 99%

“…The covalent bonds crossing the boundary between the QM and MM regions were treated by introducing three 'HQ' link atoms, 4,6,13 which are included in the QM system (62 atoms in total). The QM/ MM approach here includes bonded and non-bonded interactions between the QM and MM systems and accounts for the essential effect of the protein on the modelled reactions.…”

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confidence: 99%

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Identification of productive inhibitor binding orientation in fatty acid amide hydrolase (FAAH) by QM/MM mechanistic modelling

et al. 2008

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Section: 11mentioning

confidence: 95%

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Identification of productive inhibitor binding orientation in fatty acid amide hydrolase (FAAH) by QM/MM mechanistic modelling

et al. 2008

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“…In vitro, FAAH can act as a hydrolytic enzyme not only for fatty-acid ethanolamides such as anandamide, but also for primary amides such as oleamide and even for esters such as 2-arachidonoylglycerol (2-AG), a major endocannabinoid ligand in the brain (35,45,46). Site-directed mutagenesis experiments have shown that this broad substrate preference may be due to a previously undescribed catalytic mechanism involving the amino acid residues lysine 142, serine 241, and serine 217 (34), whose energetic aspects have been investigated by computational methods (29).…”

Section: Fatty-acid Amide Hydrolase (Faah)mentioning

confidence: 99%

Pharmacological Profile of the Selective FAAH Inhibitor KDS-4103 (URB597)

et al. 2006

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In the present article, we review the pharmacological properties of KDS-4103 (URB597), a highly potent and selective inhibitor of the enzyme fatty-acid amide hydrolase (FAAH), which catalyzes the intracellular hydrolysis of the endocannabinoid anandamide. In vitro, KDS-4103 inhibits FAAH activity with median inhibitory concentrations (IC 50 ) of 5 nM in rat brain membranes and 3 nM in human liver microsomes. In vivo, KDS-4103 inhibits rat brain FAAH activity after intraperitoneal (i.p.) administration with a median inhibitory dose (ID 50 ) of 0.15 mg/kg. The compound does not significantly interact with other cannabinoid-related targets, including cannabinoid receptors and anandamide transport, or with a broad panel of receptors, ion channels, transporters and enzymes. By i.p. administration to rats and mice KDS-4103 elicits significant, anxiolytic-like, antidepressant-like and analgesic effects, which are prevented by treatment with CB1 receptor antagonists. By contrast, at doses that significantly inhibit FAAH activity and substantially raise brain anandamide levels, KDS-4103 does not evoke classical cannabinoid-like effects (e.g., catalepsy, hypothermia, hyperphagia), does not cause place preference, and does not produce generalization to the discriminative effects of the active ingredient of cannabis, Ä 9 -tetrahydrocannabinol (Ä 9 -THC). These findings suggest that KDS-4103 acts by enhancing the tonic actions of anandamide on a subset of CB 1 receptors, which may Address correspondence and reprint requests to: Daniele Piomelli, PhD, Department of Pharmacology, 360 MSR II, University of California, Irvine, CA 92697-4625, USA; Tel.: +1 (949) 824-6180, Fax: +1 (949) 824-6305, E-mail: piomelli@uci.edu normally be engaged in controlling emotions and pain. KDS-4103 is orally available in rats and cynomolgus monkeys. Sub-chronic repeated dose studies (1500 mg/kg, per os) in these two species have not demonstrated systemic toxicity. Likewise, no toxicity was noted in bacterial cytotoxicity tests in vitro and in the Ames test. Furthermore, no deficits were observed in rats on the rotarod test after acute i.p. treatment with KDS-4103 at doses up to 5 mg/kg or in a functional observation battery after oral doses up to 1500 mg/kg. The results suggest that KDS-4103 will offer a novel approach with a favorable therapeutic window for the treatment of anxiety, depression and pain.

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“…4 shows the resulting B3LYP/6-31+G(d)//PM3-CHARMM22 energy profiles for carbamoylation of Ser241 by URB524 (blue), URB694 (red) and URB618 (green), starting from the corresponding Michaelis complexes (A). The reaction starts with a double proton transfer, in which Lys142, in cooperation with the bridging Ser217, 3 deprotonates Ser241, triggering the nucleophilic attack and formation of the TI (C).…”

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Understanding the role of carbamate reactivity in fatty acid amide hydrolase inhibition by QM/MM mechanistic modelling

et al. 2011

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QM/MM modelling of FAAH inactivation by O-biphenyl-3-yl carbamates identifies the deprotonation of Ser241 as the key reaction step, explaining why FAAH is insensitive to the electrondonor effect of conjugated substituents; this may aid design of new inhibitors with improved selectivity and in vivo potency.Carbamate-based compounds are widely used as covalent inhibitors of serine hydrolases of therapeutic interest, including fatty acid amide hydrolase (FAAH). 1 This enzyme is characterized by an uncommon Ser-Ser-Lys catalytic triad. It is the main enzyme responsible for the hydrolysis of the endocannabinoid anandamide. Despite its unusual catalytic mechanism, 2-4 FAAH is inhibited by classical serine hydrolase inhibitors, 1 and by O-biphenyl-3-yl carbamates, which are promising clinical candidates for the treatment of central nervous system and peripheral disorders. 5 These carbamate inhibitors, e.g. URB524 (Fig. 1), can be docked in two possible orientations (called orientations I and II) within the FAAH catalytic site. 6,7 Recently, hybrid quantum mechanical/molecular mechanics (QM/MM) modelling, 8 using the B3LYP/6-31G(d)//PM3-CHARMM22 potential, showed that the inhibitory process is energetically preferred in orientation II. 9 This orientation allows the catalytic nucleophile, Ser241, to efficiently attack the carbonyl group of URB524 (Fig. 2), yielding a carbamoylated enzyme. 10

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QM/MM modelling of oleamide hydrolysis in fatty acid amide hydrolase (FAAH) reveals a new mechanism of nucleophile activation

Cited by 65 publications

References 22 publications

Identification of productive inhibitor binding orientation in fatty acid amide hydrolase (FAAH) by QM/MM mechanistic modelling

Identification of productive inhibitor binding orientation in fatty acid amide hydrolase (FAAH) by QM/MM mechanistic modelling

Pharmacological Profile of the Selective FAAH Inhibitor KDS-4103 (URB597)

Understanding the role of carbamate reactivity in fatty acid amide hydrolase inhibition by QM/MM mechanistic modelling

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