Issue 9, 2011
From the journal:

Chemical Communications

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

Alessio Lodola,*a   Luigi Capoferri,a   Silvia Rivara,a   Ewa Chudyk,b   Jitnapa Sirirak,b   Edyta Dyguda-Kazimierowicz,c   W. Andrzej Sokalski,c   Mauro Mileni,d   Giorgio Tarzia,e   Daniele Piomelli,f   Marco Mora  and  Adrian J. Mulholland*b  

* Corresponding authors

a Dipartimento Farmaceutico, Università degli Studi di Parma, 43124 Parma, Italy
E-mail: Alessio.Lodola@unipr.it

b School of Chemistry, University of Bristol, Bristol, UK
E-mail: Adrian.Mulholland@bristol.ac.uk

c Department of Chemistry, Wrocław University of Technology, Wyb. Wyspianskiego 27, Wrocław, Poland

d Department of Molecular Biology, The Scripps Research Institute, La Jolla, USA

e Dipartimento di Scienze del Farmaco e della Salute, Università degli Studi di Urbino “Carlo Bo”, 61029 Urbino, Italy

f Department of Drug Discovery and Development, Italian Institute of Technology, Genova, Italy

Abstract

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 electron-donor effect of conjugated substituents; this may aid design of new inhibitors with improved selectivity and in vivo potency.

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

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Article information

DOI
https://doi.org/10.1039/C0CC04937A
Article type
Communication
Submitted
12 Nov 2010
Accepted
21 Dec 2010
First published
14 Jan 2011

Chem. Commun., 2011,47, 2517-2519

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

A. Lodola, L. Capoferri, S. Rivara, E. Chudyk, J. Sirirak, E. Dyguda-Kazimierowicz, W. Andrzej Sokalski, M. Mileni, G. Tarzia, D. Piomelli, M. Mor and A. J. Mulholland, Chem. Commun., 2011, 47, 2517 DOI: 10.1039/C0CC04937A

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