47. Romero FA, Du W, Hwang I, Rayl TJ, Kimball FS, Leung D, Hoover HS, Apodaca RL,
Breitenbucher JG, Cravatt BF, Boger DL (2007) Potent and selective alpha-ketoheterocyclebased inhibitors of the anandamide and oleamide catabolizing enzyme, fatty acid amide
hydrolase. J Med Chem 50(5):1058–1068. doi:10.1021/jm0611509
48. Ahn K, Johnson DS, Fitzgerald LR, Liimatta M, Arendse A, Stevenson T, Lund ET, Nugent
RA, Nomanbhoy TK, Alexander JP, Cravatt BF (2007) Novel mechanistic class of fatty acid
amide hydrolase inhibitors with remarkable selectivity. Biochemistry 46(45):13019–13030.
doi:10.1021/bi701378g
49. Minkkila A, Saario S, Nevalainen T (2010) Discovery and development of endocannabinoidhydrolyzing enzyme inhibitors. Curr Top Med Chem 10(8):828–858. doi:BSP/ CTMC /EPub/-0051-10-8 [pii]
50. Johnson DS, Stiff C, Lazerwith SE, Kesten SR, Fay LK, Morris M, Beidler D, Liimatta MB,
Smith SE, Dudley DT, Sadagopan N, Bhattachar SN, Kesten SJ, Nomanbhoy TK, Cravatt BF,
Ahn K (2011) Discovery of PF-04457845: a highly potent, orally bioavailable, and selective
urea FAAH inhibitor. Acs Med Chem Lett 2(2):91–96. doi:10.1021/ml100190t
51. Patricelli MP, Cravatt BF (2000) Clarifying the catalytic roles of conserved residues in the
amidase signature family. J Biol Chem 275(25):19177–19184. doi:10.1074/jbc.M001607200
M001607200 [pii]
52. Tubert-Brohman I, Acevedo O, Jorgensen WL (2006) Elucidation of hydrolysis mechanisms
for fatty acid amide hydrolase and its Lys142Ala variant via QM/MM simulations. J Am
Chem Soc 128(51):16904–16913. doi:10.1021/ja065863s
53. Lodola A, Mor M, Hermann JC, Tarzia G, Piomelli D, Mulholland AJ (2005) QM/MM
modelling of oleamide hydrolysis in fatty acid amide hydrolase (FAAH) reveals a new
mechanism of nucleophile activation. Chem Commun (Camb) 35:4399–4401. doi:10.1039/
b503887a
54. Capoferri L, Mor M, Sirirak J, Chudyk E, Mulholland AJ, Lodola A (2011) Application of a
SCC-DFTB QM/MM approach to the investigation of the catalytic mechanism of fatty acid
amide hydrolase. J Mol Model 17(9):2375–2383. doi:10.1007/s00894-011-0981-z
55. Lodola A, Sirirak J, Fey N, Rivara S, Mor M, Mulholland AJ (2010) Structural fluctuations in
enzyme-catalyzed reactions: determinants of reactivity in fatty acid amide hydrolase from
multivariate statistical analysis of quantum mechanics/molecular mechanics paths. J Chem
Theory Comput 6(9):2948–2960. doi:10.1021/ct100264j
56. Lodola A, Mor M, Zurek J, Tarzia G, Piomelli D, Harvey JN, Mulholland AJ (2007)
Conformational effects in enzyme catalysis: Reaction via a high energy conformation in fatty
acid amide hydrolase. Biophys J 92(2):L20–L22. doi:10.1529/biophysj.106.098434
57. Bowman AL, Makriyannis A (2011) Approximating protein flexibility through dynamic
pharmacophore models: application to fatty acid amide hydrolase (FAAH). J Chem Inf Model
51(12):3247–3253. doi:10.1021/ci200371z
58. Palermo G, Branduardi D, Masetti M, Lodola A, Mor M, Piomelli D, Cavalli A, De Vivo M
(2011) Covalent inhibitors of fatty acid amide hydrolase: a rationale for the activity of
piperidine and piperazine aryl ureas. J Med Chem 54(19):6612–6623. doi:10.1021/jm2004283
59. Lodola A, Mor M, Rivara S, Christov C, Tarzia G, Piomelli D, Mulholland AJ (2008)
Identification of productive inhibitor binding orientation in fatty acid amide hydrolase (FAAH)
by QM/MM mechanistic modelling. Chem Commun (Camb) 2:214–216. doi:10.1039/
b714136j
60. Case DA, Darden TA, T. E. Cheatham I, Simmerling CL, Wang J, Duke RE, Luo R, Crowley
M, Walker RC, Zhang W, Merz KM, Wang B, Hayik S, Roitberg A, Seabra G, Kolossváry I,
Wong KF, Paesani F, Vanicek J, Wu X, Brozell SR, Steinbrecher T, Gohlke H, Yang L, Tan
C, Mongan J, Hornak V, Cui G, Mathews DH, Seetin MG, Sagui C, Babin V, Kollman PA
(2008) AMBER 10. San Francisco
61. Duan Y, Wu C, Chowdhury S, Lee MC, Xiong G, Zhang W, Yang R, Cieplak P, Luo R, Lee
T, Caldwell J, Wang J, Kollman P (2003) A point-charge force field for molecular mechanics
simulations of proteins based on condensed-phase quantum mechanical calculations. J Comput
Chem 24(16):1999–2012. doi:10.1002/jcc.10349
130
S.F. Sousa et al.
Breitenbucher JG, Cravatt BF, Boger DL (2007) Potent and selective alpha-ketoheterocyclebased inhibitors of the anandamide and oleamide catabolizing enzyme, fatty acid amide
hydrolase. J Med Chem 50(5):1058–1068. doi:10.1021/jm0611509
48. Ahn K, Johnson DS, Fitzgerald LR, Liimatta M, Arendse A, Stevenson T, Lund ET, Nugent
RA, Nomanbhoy TK, Alexander JP, Cravatt BF (2007) Novel mechanistic class of fatty acid
amide hydrolase inhibitors with remarkable selectivity. Biochemistry 46(45):13019–13030.
doi:10.1021/bi701378g
49. Minkkila A, Saario S, Nevalainen T (2010) Discovery and development of endocannabinoidhydrolyzing enzyme inhibitors. Curr Top Med Chem 10(8):828–858. doi:BSP/ CTMC /EPub/-0051-10-8 [pii]
50. Johnson DS, Stiff C, Lazerwith SE, Kesten SR, Fay LK, Morris M, Beidler D, Liimatta MB,
Smith SE, Dudley DT, Sadagopan N, Bhattachar SN, Kesten SJ, Nomanbhoy TK, Cravatt BF,
Ahn K (2011) Discovery of PF-04457845: a highly potent, orally bioavailable, and selective
urea FAAH inhibitor. Acs Med Chem Lett 2(2):91–96. doi:10.1021/ml100190t
51. Patricelli MP, Cravatt BF (2000) Clarifying the catalytic roles of conserved residues in the
amidase signature family. J Biol Chem 275(25):19177–19184. doi:10.1074/jbc.M001607200
M001607200 [pii]
52. Tubert-Brohman I, Acevedo O, Jorgensen WL (2006) Elucidation of hydrolysis mechanisms
for fatty acid amide hydrolase and its Lys142Ala variant via QM/MM simulations. J Am
Chem Soc 128(51):16904–16913. doi:10.1021/ja065863s
53. Lodola A, Mor M, Hermann JC, Tarzia G, Piomelli D, Mulholland AJ (2005) QM/MM
modelling of oleamide hydrolysis in fatty acid amide hydrolase (FAAH) reveals a new
mechanism of nucleophile activation. Chem Commun (Camb) 35:4399–4401. doi:10.1039/
b503887a
54. Capoferri L, Mor M, Sirirak J, Chudyk E, Mulholland AJ, Lodola A (2011) Application of a
SCC-DFTB QM/MM approach to the investigation of the catalytic mechanism of fatty acid
amide hydrolase. J Mol Model 17(9):2375–2383. doi:10.1007/s00894-011-0981-z
55. Lodola A, Sirirak J, Fey N, Rivara S, Mor M, Mulholland AJ (2010) Structural fluctuations in
enzyme-catalyzed reactions: determinants of reactivity in fatty acid amide hydrolase from
multivariate statistical analysis of quantum mechanics/molecular mechanics paths. J Chem
Theory Comput 6(9):2948–2960. doi:10.1021/ct100264j
56. Lodola A, Mor M, Zurek J, Tarzia G, Piomelli D, Harvey JN, Mulholland AJ (2007)
Conformational effects in enzyme catalysis: Reaction via a high energy conformation in fatty
acid amide hydrolase. Biophys J 92(2):L20–L22. doi:10.1529/biophysj.106.098434
57. Bowman AL, Makriyannis A (2011) Approximating protein flexibility through dynamic
pharmacophore models: application to fatty acid amide hydrolase (FAAH). J Chem Inf Model
51(12):3247–3253. doi:10.1021/ci200371z
58. Palermo G, Branduardi D, Masetti M, Lodola A, Mor M, Piomelli D, Cavalli A, De Vivo M
(2011) Covalent inhibitors of fatty acid amide hydrolase: a rationale for the activity of
piperidine and piperazine aryl ureas. J Med Chem 54(19):6612–6623. doi:10.1021/jm2004283
59. Lodola A, Mor M, Rivara S, Christov C, Tarzia G, Piomelli D, Mulholland AJ (2008)
Identification of productive inhibitor binding orientation in fatty acid amide hydrolase (FAAH)
by QM/MM mechanistic modelling. Chem Commun (Camb) 2:214–216. doi:10.1039/
b714136j
60. Case DA, Darden TA, T. E. Cheatham I, Simmerling CL, Wang J, Duke RE, Luo R, Crowley
M, Walker RC, Zhang W, Merz KM, Wang B, Hayik S, Roitberg A, Seabra G, Kolossváry I,
Wong KF, Paesani F, Vanicek J, Wu X, Brozell SR, Steinbrecher T, Gohlke H, Yang L, Tan
C, Mongan J, Hornak V, Cui G, Mathews DH, Seetin MG, Sagui C, Babin V, Kollman PA
(2008) AMBER 10. San Francisco
61. Duan Y, Wu C, Chowdhury S, Lee MC, Xiong G, Zhang W, Yang R, Cieplak P, Luo R, Lee
T, Caldwell J, Wang J, Kollman P (2003) A point-charge force field for molecular mechanics
simulations of proteins based on condensed-phase quantum mechanical calculations. J Comput
Chem 24(16):1999–2012. doi:10.1002/jcc.10349
130
S.F. Sousa et al.