Journal of Medicinal Chemistry
Article
metabolism in chemicals. Drug Discovery Today: Technol. 2013, 10,
e155−e165.
adenosine A(1), A (2A), A (2B), and A (3) receptor antagonists. J.
Comput.-Aided Mol. Des. 2012, 26, 1247−1266.
(45) Goodford, P. J. The basic principles of GRID. In Molecular
Interaction Fields: Applications in Drug Discovery and ADME Prediction;
Cruciani, G., Ed.; Wiley-VCH: Weinheim, Germany, 2006; pp 1−25.
1, 2014).
(29) Shiraga, T.; Yajima, K.; Teragaki, T.; Suzuki, K.; Hashimoto, T.;
Iwatsubo, T.; Miyashita, A.; Usui, T. Identification of enzymes
responsible for the N-oxidation of darexaban glucuronide, the
pharmacologically active metabolite of darexaban, and the glucur-
onidation of darexaban N-oxides in human liver microsomes. Biol.
Pharm. Bull. 2012, 35, 413−421.
(47) Rosipal, R.; Kramer, N. Overview and recent advances in partial
least squares. In Subspace, Latent Structure and Feature Selection:
Statistical and Optimization Perspectives Workshop (SLSFS 2005);
Saunders, C., et al., Eds.; Springer-Verlag: New York, 2006; pp 34−51.
(48) Cruciani, G.; Carosati, E.; De Boeck, B.; Ethirajulu, K.; Mackie,
C.; Howe, T.; Vianello, R. MetaSite: understanding metabolism in
human cytochromes from the perspective of the chemist. J. Med. Chem.
2005, 48, 6970−6979.
(49) Yanni, S. B.; Annaert, P. P.; Augustijns, P.; Ibrahim, J. G.;
Benjamin, D. K., Jr.; Thakker, D. R. In vitro hepatic metabolism
explains higher clearance of voriconazole in children versus adults: role
of CYP2C19 and flavin-containing monooxygenase 3. Drug Metab.
Dispos. 2010, 38, 25−31.
(50) Vyas, P. M.; Roychowdhury, S.; Koukouritaki, S. B.; Hines, R.
N.; Krueger, S. K.; Williams, D. E.; Nauseef, W. M.; Svensson, C. K.
Enzyme-mediated protein haptenation of dapsone and sulfamethox-
azole in human keratinocytes: II. Expression and role of flavin-
containing monooxygenases and peroxidases. J. Pharmacol. Exp. Ther.
2006, 319, 497−505.
(51) Alinezhad, H.; Tajbakhsh, M.; Mahdavi, N. One-pot reductive
amination of carbonyl compounds using sodium borohydride-
amberlist 15. Synth. Commun. 2010, 40, 951−956.
(52) O’Connor, S.; Dumas, J.; Lee, W.; Dixon, J.; Cantin, D.; Gunn,
D.; Burke, J.; Phillips, B.; Lowe, D.; Shelekhin, T.; Wang, G.; Ma, X.;
Ying, S.; McClure, A.; Achebe, F.; Lobell, M.; Ehrgott, F.; Iwuagwu,
C.; Parcella, K. Pirrolo[2,1-F][1,2,4]triazin-4-ylamines IGF-1R kinase
inhibitors for the treatment of cancer and other hyperproliferative
diseases. U.S. Patent US20110294776 A1, Dec 1, 2011.
(53) Bonn, B.; Leandersson, C.; Fontaine, F.; Zamora, I. Enhanced
metabolite identification with MS(E) and a semi-automated software
for structural elucidation. Rapid Commun. Mass Spectrom. 2010, 24,
3127−3138.
(54) Zamora, I.; Fontaine, F.; Serra, B.; Plasencia, G. High-
throughput, fully automated, specific MetID. A revolution for drug
discovery. Drug Discovery Today: Technol. 2013, 10, e199−205.
(55) Zhang, Y. I-TASSER server for protein 3D structure prediction.
BMC Bioinf. 2008, 9, 40.
(30) Jacobsen, W.; Christians, U.; Benet, L. Z. In vitro evaluation of
the disposition of A novel cysteine protease inhibitor. Drug Metab.
Dispos. 2000, 28, 1343−1351.
(31) Ohmi, N.; Yoshida, H.; Endo, H.; Hasegawa, M.; Akimoto, M.;
Higuchi, S. S-oxidation of S-methyl-esonarimod by flavin-containing
monooxygenases in human liver microsomes. Xenobiotica 2003, 33,
1221−1231.
(32) Xie, G.; Wong, C. C.; Cheng, K. W.; Huang, L.; Constantinides,
P. P.; Rigas, B. Regioselective oxidation of phospho-NSAIDs by
human cytochrome P450 and flavin monooxygenase isoforms:
implications for their pharmacokinetic properties and safety. Br. J.
Pharmacol. 2012, 16, 222−232.
(33) Attar, M.; Dong, D.; Ling, K. H.; Tang-Liu, D. D. Cytochrome
P450 2C8 and flavin-containing monooxygenases are involved in the
metabolism of tazarotenic acid in humans. Drug Metab. Dispos. 2003,
31, 476−481.
(34) Kajita, J.; Inano, K.; Fuse, E.; Kuwabara, T.; Kobayashi, H.
Effects of olopatadine, a new antiallergic agent, on human liver
microsomal cytochrome P450 activities. Drug Metab. Dispos. 2002, 30,
1504−1511.
(35) Ripp, S. L.; Overby, L. H.; Philpot, R. M.; Elfarra, A. A.
Oxidation of cysteine S-conjugates by rabbit liver microsomes and
cDNA-expressed flavin-containing mono-oxygenases: studies with S-
(1,2-dichlorovinyl)-L-cysteine, S-(1,2,2-trichlorovinyl)-L-cysteine, S-
allyl-L-cysteine, and S-benzyl-L-cysteine. Mol. Pharmacol. 1997, 51,
507−515.
(36) Dever, J. T.; Elfarra, A. A. In vivo metabolism of L-methionine
in mice: evidence for stereoselective formation of methionine-d-
sulfoxide and quantitation of other major metabolites. Drug Metab.
Dispos. 2006, 34, 2036−2043.
(37) el Amri, H. S.; Fargetton, X.; Delatour, P.; Batt, A. M.
Sulphoxidation of albendazole by the FAD-containing and cytochrome
P-450 dependent mono-oxygenases from pig liver microsomes.
Xenobiotica 1987, 17, 1159−1168.
(38) Furnes, B.; Schlenk, D. Extrahepatic metabolism of carbamate
and organophosphate thioether compounds by the flavin-containing
monooxygenase and cytochrome P450 systems. Drug Metab. Dispos.
2005, 33, 214−218.
(39) Milletti, F.; Storchi, L.; Sforna, G.; Cruciani, G. New and
original pKa prediction method using grid molecular interaction fields.
J. Chem. Inf. Model. 2007, 47, 2172−2181.
(40) Cruciani, G.; Milletti, F.; Storchi, L.; Sforna, G.; Goracci, L. In
silico pKa prediction and ADME profiling. Chem. Biodiversity 2009, 6,
1812−1821.
(41) Alfieri, A.; Malito, E.; Orru, R.; Fraaije, M. W.; Mattevi, A.
Revealing the moonlighting role of NADP in the structure of a flavin-
containing monooxygenase. Proc. Natl. Acad. Sci. U.S.A. 2008, 105,
6572−6577.
(42) Koukouritaki, S. B.; Poch, M. T.; Henderson, M. C.; Siddens, L.
K.; Krueger, S. K.; VanDyke, J. E.; Williams, D. E.; Pajewski, N. M.;
Wang, T.; Hines, R. N. Identification and functional analysis of
common human flavin-containing monooxygenase 3 genetic variants.
J. Pharmacol. Exp. Ther. 2007, 320, 266−273.
TASSER/ (accessed February 12, 2014).
(57) Case, D. A.; Darden, T. A.; Cheatham, T. E., III; Simmerling, C.
L.; Wang, J.; Duke, R. E.; Luo, R.; Walker, R. C.; Zhang, W.; Merz, K.
M.; Roberts, B.; Hayik, S.; Roitberg, A.; Seabra, G.; Swails, J.; Goetz, A.
́
W.; Kolossvary, I.; Wong, K. F.; Paesani, F.; Vanicek, J.; Wolf, R. M.;
Liu, J.; Wu, X.; Brozell, S. R.; Steinbrecher, T.; Gohlke, H.; Cai, Q.; Ye,
X.; Wang, J.; Hsieh, M.-J.; Cui, G.; Roe, D. R.; Mathews, D. H.; Seetin,
M. G.; Salomon-Ferrer, R.; Sagui, C.; Babin, V.; Luchko, T.; Gusarov,
S.; Kovalenko, A.; Kollman, P. A. AMBER 12; University of California:
San Francisco, CA. 2012.
(58) Jorgensen, W. L.; Chandrasekhar, J.; Madura, J. D.; Impey, R.
W.; Klein, M. L. Comparison of simple potential functions for
simulating liquid water. J. Chem. Phys. 1983, 79, 926−935.
(59) Hess, B.; Kutzner, C.; van der Spoel, D.; Lindahl, E. GROMACS
4: algorithms for highly efficient, load-balanced, and scalable molecular
simulation. J. Chem. Theory Comput. 2008, 4, 435−447.
(60) Hess, B.; Bekker, H.; Berendsen, H. J. C.; Fraaije, J. G. E. M.
Lincs: a linear constraint solver for molecular simulations. J. Comput.
Chem. 1997, 18, 1463−1472.
(61) Shao, Y.; Molnar, L. F.; Jung, Y.; Kussmann, J.; Ochsenfeld, C.;
Brown, S. T.; Gilbert, A. T. B.; Slipchenko, L. V.; Levchenko, S. V.;
O’Neill, D. P.; DiStasio, R. A., Jr.; Lochan, R. C.; Wang, T.; Beran, G. J.
O.; Besley, N. A.; Herbert, J. M.; Lin, C. Y.; Van Voorhis, T.; Chien, S.
(43) Baroni, M.; Cruciani, G.; Sciabola, S.; Perruccio, F.; Mason, J. S.
A common reference framework for analyzing/comparing proteins and
ligands. Fingerprints for ligands and proteins (FLAP): theory and
application. J. Chem. Inf. Model. 2007, 47, 279−294.
(44) Sirci, F.; Goracci, L.; Rodríguez, D.; van Muijlwijk-Koezen, J.;
Gutier
́ ́
rez-de-Teran, H.; Mannhold, R. Ligand-, structure- and
pharmacophore-based molecular fingerprints: a case study on
M
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