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

Alessio Lodola; Marco Mor; Jitnapa Sirirak; Adrian J. Mulholland

doi:10.1042/BST0370363

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

Alessio Lodola, Marco Mor, Jitnapa Sirirak, Adrian J. Mulholland^*

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

34 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	363-367
Number of pages	5
Journal	Biochemical Society Transactions
Volume	37
Issue number	2
DOIs	https://doi.org/10.1042/BST0370363
Publication status	Published - 2009

Keywords

Fatty acid amide hydrolase (FAAH)
Inhibitor design
Quantum mechanics/molecular mechanics (QM/MM)
Reaction mechanism
Tetrahedral intermediate
Transition state

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abstract = "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.",

keywords = "Fatty acid amide hydrolase (FAAH), Inhibitor design, Quantum mechanics/molecular mechanics (QM/MM), Reaction mechanism, Tetrahedral intermediate, Transition state",

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T1 - Insights into the mechanism and inhibition of fatty acid amide hydrolase from quantum mechanics/molecular mechanics (QM/MM) modelling

AU - Lodola, Alessio

AU - Mor, Marco

AU - Sirirak, Jitnapa

AU - Mulholland, Adrian J.

PY - 2009

Y1 - 2009

N2 - 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.

AB - 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.

KW - Fatty acid amide hydrolase (FAAH)

KW - Inhibitor design

KW - Quantum mechanics/molecular mechanics (QM/MM)

KW - Reaction mechanism

KW - Tetrahedral intermediate

KW - Transition state

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SN - 0300-5127

VL - 37

SP - 363

EP - 367

JO - Biochemical Society Transactions

JF - Biochemical Society Transactions

IS - 2

ER -

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

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COMPUTATIONAL BIOCHEMISTRY: PREDICTIVE MODELLING FOR BIOLOGY AND MEDICINE

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

Abstract

Keywords

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COMPUTATIONAL BIOCHEMISTRY: PREDICTIVE MODELLING FOR BIOLOGY AND MEDICINE

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