H. J. Berendsen, J. R. Grigera, and T. P. Straatsma, The missing term in effective pair potentials, The Journal of Physical Chemistry, vol.91, issue.24, pp.916269-6271, 1987.
DOI : 10.1021/j100308a038

H. J. Berendsen, J. P. Postma, W. F. Van-gunsteren, A. Dinola, and J. R. Haak, Molecular dynamics with coupling to an external bath, The Journal of Chemical Physics, vol.81, issue.8, p.813684, 1984.
DOI : 10.1063/1.448118

H. Böhm, Prediction of binding constants of protein ligands: A fast method for the prioritization of hits obtained from de novo design or 3D database search programs, Journal of Computer-Aided Molecular Design, vol.12, issue.4, p.309, 1998.
DOI : 10.1023/A:1007999920146

D. Bourgeois and A. Royant, Advances in kinetic protein crystallography, Current Opinion in Structural Biology, vol.15, issue.5, pp.538-585, 2005.
DOI : 10.1016/j.sbi.2005.08.002

D. Bourgeois, B. Vallone, F. Schotte, A. Arcovito, A. E. Miele et al., Complex landscape of protein structural dynamics unveiled by nanosecond Laue crystallography, Proceedings of the National Academy of Sciences of the United States of America, pp.8704-8713, 2003.
DOI : 10.1073/pnas.1430900100

D. Bourgeois and M. Weik, Kinetic protein crystallography: a tool to watch proteins in action, Crystallography Reviews, vol.71, issue.2, pp.87-118, 2009.
DOI : 10.1080/08893110802604868

Y. Bourne, H. C. Kolb, Z. Radi?, K. B. Sharpless, P. Taylor et al., Freeze-frame inhibitor captures acetylcholinesterase in a unique conformation, Proceedings of the National Academy of Sciences of the United States of America, pp.1449-54, 2004.
DOI : 10.1073/pnas.0308206100

Y. Bourne, Z. Radic, G. Sulzenbacher, E. Kim, P. Taylor et al., Substrate and Product Trafficking through the Active Center Gorge of Acetylcholinesterase Analyzed by Crystallography and Equilibrium Binding, Journal of Biological Chemistry, vol.281, issue.39, pp.28129256-67, 2006.
DOI : 10.1074/jbc.M603018200

URL : https://hal.archives-ouvertes.fr/hal-00134313

Y. Bourne, Z. Radi?, P. Taylor, and P. Marchot, Conformational Remodeling of Femtomolar Inhibitor???Acetylcholinesterase Complexes in the Crystalline State, Journal of the American Chemical Society, vol.132, issue.51, pp.13218292-300, 2010.
DOI : 10.1021/ja106820e

URL : https://hal.archives-ouvertes.fr/hal-00625332

M. Harel, J. L. Sussman, E. Krejci, S. Bon, P. Chanal et al., Conversion of acetylcholinesterase to butyrylcholinesterase: modeling and mutagenesis., Proceedings of the National Academy of Sciences of the United States of America, pp.8910827-8910858, 1992.
DOI : 10.1073/pnas.89.22.10827

M. Hartenfeller and G. Schneider, De Novo Drug Design, Methods in molecular biology, vol.672, pp.299-323, 2011.
DOI : 10.1007/978-1-60761-839-3_12

W. Hendrickson, Determination of macromolecular structures from anomalous diffraction of synchrotron radiation, Science, vol.254, issue.5028, pp.51-58, 1991.
DOI : 10.1126/science.1925561

B. Henrich, A. Bergamaschi, C. Broennimann, R. Dinapoli, E. Eikenberry et al., PILATUS: A single photon counting pixel detector for X-ray applications. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, pp.247-249, 2009.

K. Henzler-wildman and D. Kern, Dynamic personalities of proteins, Nature, vol.124, issue.7172, pp.964-72, 2007.
DOI : 10.1038/nature06522

K. Henzler-wildman, M. Lei, V. Thai, S. J. Kerns, M. Karplus et al., A hierarchy of timescales in protein dynamics is linked to enzyme catalysis, Nature, vol.21, issue.7171, pp.450913-450919, 2007.
DOI : 10.1038/nature06407

R. P. Hertzberg and A. J. Pope, High-throughput screening: new technology for the 21st century, Current Opinion in Chemical Biology, vol.4, issue.4, pp.445-451, 2000.
DOI : 10.1016/S1367-5931(00)00110-1

B. Hess, H. Bekker, H. J. Berendsen, and J. G. Fraaije, LINCS: A linear constraint solver for molecular simulations, Journal of Computational Chemistry, issue.12, pp.181463-1472, 1997.

B. Hess, C. Kutzner, D. Van-der-spoel, and E. Lindahl, GROMACS 4:?? Algorithms for Highly Efficient, Load-Balanced, and Scalable Molecular Simulation, Journal of Chemical Theory and Computation, vol.4, issue.3, pp.435-447, 2008.
DOI : 10.1021/ct700301q

A. Hörnberg, E. Artursson, R. Wärme, Y. Pang, and F. Ekström, Crystal structures of oxime-bound fenamiphos-acetylcholinesterases: reactivation BIBLIOGRAPHY involving flipping of the His447 ring to form a reactive Glu334-His447-oxime triad, Biochemical pharmacology, issue.3, pp.79507-79522, 2010.

J. D. Hunter, Matplotlib: A 2D Graphics Environment, Computing in Science & Engineering, vol.9, issue.3, pp.90-95, 2007.
DOI : 10.1109/MCSE.2007.55

J. J. Irwin, T. Sterling, M. M. Mysinger, E. S. Bolstad, C. et al., ZINC: A Free Tool to Discover Chemistry for Biology, Journal of Chemical Information and Modeling, vol.52, issue.7, pp.521757-68, 2012.
DOI : 10.1021/ci3001277

C. J. Jackson, J. Liu, P. D. Carr, F. Younus, C. Coppin et al., Structure and function of an insect ?-carboxylesterase (?Esterase7) associated with insecticide resistance, Proceedings of the National Academy of Sciences of the United States of America, pp.11010177-82, 2013.

M. Jacobsson, P. Lidén, E. Stjernschantz, H. Boström, and U. Norinder, Improving Structure-Based Virtual Screening by Multivariate Analysis of Scoring Data, Journal of Medicinal Chemistry, vol.46, issue.26, pp.465781-465790, 2003.
DOI : 10.1021/jm030896t

A. N. Jain, Virtual screening in lead discovery and optimization. Current opinion in drug discovery & development, pp.396-403, 2004.

A. N. Jain, Scoring functions for protein-ligand docking, Current protein & peptide science, vol.7, issue.5, pp.407-427, 2006.

G. Jones, P. Willett, R. C. Glen, A. R. Leach, T. et al., Development and validation of a genetic algorithm for flexible docking, Journal of Molecular Biology, vol.267, issue.3, pp.727-775, 1997.
DOI : 10.1006/jmbi.1996.0897

W. L. Jorgensen, J. Chandrasekhar, J. D. Madura, R. W. Impey, and M. L. Klein, Comparison of simple potential functions for simulating liquid water, The Journal of Chemical Physics, vol.79, issue.2, p.79926, 1983.
DOI : 10.1063/1.445869

D. H. Juers and B. W. Matthews, Cryo-cooling in macromolecular crystallography: advantages, disadvantages and optimization, Quarterly Reviews of Biophysics, vol.37, issue.2, pp.105-119, 2004.
DOI : 10.1017/S0033583504004007

A. L. Perrier, J. Massoulié, and E. Krejci, PRiMA, Neuron, vol.33, issue.2, pp.275-285, 2002.
DOI : 10.1016/S0896-6273(01)00584-0

E. F. Pettersen, T. D. Goddard, C. C. Huang, G. S. Couch, D. M. Greenblatt et al., UCSF Chimera?A visualization system for exploratory research and analysis, Journal of Computational Chemistry, vol.373, issue.13, pp.251605-251617, 2004.
DOI : 10.1002/jcc.20084

D. M. Quinn, Acetylcholinesterase: enzyme structure, reaction dynamics, and virtual transition states, Chemical Reviews, vol.87, issue.5, pp.955-979, 1987.
DOI : 10.1021/cr00081a005

R. B. Ravelli and S. M. Mcsweeney, The ???fingerprint??? that X-rays can leave on structures, Structure, vol.8, issue.3, pp.315-343, 1993.
DOI : 10.1016/S0969-2126(00)00109-X

D. Rochu, E. Chabrière, and P. Masson, Human paraoxonase: A promising approach for pre-treatment and therapy of organophosphorus poisoning, Toxicology, vol.233, issue.1-3, pp.1-347, 2007.
DOI : 10.1016/j.tox.2006.08.037

URL : https://hal.archives-ouvertes.fr/hal-00207585

M. Rogers-evans, A. Alanine, K. Bleicher, D. Kube, and G. Schneider, Identification of novel cannabinoid receptor ligandsvia evolutionary de novo design and rapid parallel synthesis, QSAR & Combinatorial Science, vol.23, issue.6, pp.426-430, 2004.
DOI : 10.1002/qsar.200410012

M. G. Rossmann and D. M. Blow, The detection of sub-units within the crystallographic asymmetric unit, Acta Crystallographica, vol.15, issue.1, pp.24-31, 1962.
DOI : 10.1107/S0365110X62000067

E. H. Rydberg, B. Brumshtein, H. M. Greenblatt, D. M. Wong, D. Shaya et al., Complexes of alkylene-linked tacrine dimers with Torpedo californica acetylcholinesterase: Binding of Bis5-tacrine produces a dramatic rearrangement in the active-site gorge, Journal of medicinal chemistry, issue.18, pp.495491-500, 2006.

B. Sanson, J. Colletier, Y. Xu, P. T. Lang, H. Jiang et al., Backdoor opening mechanism in acetylcholinesterase based on X-ray crystallography and molecular dynamics simulations Protein science : a publication of the, pp.1114-1122, 2011.

L. Savini, A. Gaeta, C. Fattorusso, B. Catalanotti, G. Campiani et al., Specific Targeting of Acetylcholinesterase and Butyrylcholinesterase Recognition Sites. Rational Design of Novel, Selective, and Highly Potent Cholinesterase Inhibitors, Journal of Medicinal Chemistry, vol.46, issue.1, pp.1-4, 2003.
DOI : 10.1021/jm0255668

J. R. Schames, R. H. Henchman, J. S. Siegel, C. A. Sotriffer, H. Ni et al., Discovery of a Novel Binding Trench in HIV Integrase, Journal of Medicinal Chemistry, vol.47, issue.8, pp.471879-81, 2004.
DOI : 10.1021/jm0341913

G. Schneider and U. Fechner, Computer-based de novo design of drug-like molecules, Nature Reviews Drug Discovery, vol.70, issue.8, pp.649-63, 2005.
DOI : 10.1073/pnas.032673399

F. Schotte, M. Lim, T. A. Jackson, A. V. Smirnov, J. Soman et al., Watching a Protein as it Functions with 150-ps Time-Resolved X-ray Crystallography, Science, vol.300, issue.5627, pp.3001944-3001951, 2003.
DOI : 10.1126/science.1078797

L. Schrödinger, The {PyMOL} Molecular Graphics System, Version?1, 2010.

D. E. Shaw, K. J. Bowers, E. Chow, M. P. Eastwood, D. J. Ierardi et al., Millisecond-scale molecular dynamics simulations on Anton, Proceedings of the Conference on High Performance Computing Networking, Storage and Analysis, SC '09, p.1, 2009.
DOI : 10.1145/1654059.1654126

I. Silman and J. L. Sussman, Acetylcholinesterase, Current opinion in pharmacology, vol.5, issue.3, pp.293-302, 2005.
DOI : 10.1007/978-1-4613-4458-2_6

URL : https://hal.archives-ouvertes.fr/hal-00120647

S. F. Sousa, .. J. Ribeiro, J. T. Coimbra, R. P. Neves, S. Martins et al., Protein-ligand, 2013.

C. F. Wong, J. Kua, Y. Zhang, T. P. Straatsma, and J. A. And-mccammon, Molecular docking of balanol to dynamics snapshots of protein kinase A, Proteins: Structure, Function, and Bioinformatics, vol.116, issue.24, pp.61850-61858, 2005.
DOI : 10.1002/prot.20688

F. Worek, T. Seeger, M. Goldsmith, Y. Ashani, H. Leader et al., Efficacy of the rePON1 mutant IIG1 to prevent cyclosarin toxicity in vivo and to detoxify structurally different nerve agents in vitro, Archives of Toxicology, vol.68, issue.83, pp.1257-66, 2014.
DOI : 10.1007/s00204-014-1204-z

F. Worek, T. Seeger, G. Reiter, M. Goldsmith, Y. Ashani et al., Post-exposure treatment of VX poisoned guinea pigs with the engineered phosphotriesterase mutant C23: A proof-of-concept study, Toxicology Letters, vol.231, issue.1, pp.45-54, 2014.
DOI : 10.1016/j.toxlet.2014.09.003

F. Worek, H. Thiermann, L. Szinicz, and P. Eyer, Kinetic analysis of interactions between human acetylcholinesterase, structurally different organophosphorus compounds and oximes, Biochemical Pharmacology, vol.68, issue.11, pp.682237-682285, 2004.
DOI : 10.1016/j.bcp.2004.07.038

Y. Xu, J. Colletier, M. Weik, G. Qin, H. Jiang et al., Long Route or Shortcut? A Molecular Dynamics Study of Traffic of Thiocholine within the Active-Site Gorge of Acetylcholinesterase, Biophysical Journal, vol.99, issue.12, pp.994003-994014, 2010.
DOI : 10.1016/j.bpj.2010.10.047

Y. Xu, J. Shen, X. Luo, I. Silman, J. L. Sussman et al., How Does Huperzine A Enter and Leave the Binding Gorge of Acetylcholinesterase? Steered Molecular Dynamics Simulations, Journal of the American Chemical Society, vol.125, issue.37, pp.12511340-12511349, 2003.
DOI : 10.1021/ja029775t

G. E. Boldt, T. J. Dicherson, K. D. Jandac-)-a, . B. Eliseevd-)-k, R. Sharpless et al., Drug Discovery Today Drug Discovery Today, Expert Opin. Drug Discovery Angew. Chem., Int. Ed, vol.9, issue.2, pp.143-148, 2002.

B. Anand and . Singh, A review on cholinesterase inhibitors for Alzheimer???s disease, Archives of Pharmacal Research, vol.16, issue.Suppl 1, pp.375-399, 2013.
DOI : 10.1007/s12272-013-0036-3

Z. Krasinski, R. Radi?, J. Manetsch, P. Raushel, K. B. Taylor et al., In Situ Selection of Lead Compounds by Click Chemistry:?? Target-Guided Optimization of Acetylcholinesterase Inhibitors, Journal of the American Chemical Society, vol.127, issue.18, pp.6686-6692, 2005.
DOI : 10.1021/ja043031t

J. Whiting, Y. Muldoon, S. M. Lin, W. Silverman, A. J. Lindstrom et al., Inhibitors of HIV-1 Protease by Using In Situ Click Chemistry, Angewandte Chemie International Edition, vol.67, issue.9, pp.1435-1439, 2006.
DOI : 10.1002/anie.200502161

P. Mocharla, B. Colasson, L. V. Lee, S. Röper, K. B. Sharpless et al., In Situ Click Chemistry: Enzyme-Generated Inhibitors of Carbonic Anhydrase II, Angewandte Chemie International Edition, vol.242, issue.1, pp.116-120, 2005.
DOI : 10.1002/anie.200461580

M. Willand, P. Desroses, B. Toto, Z. Dirié, V. Lens et al., Click Chemistry: Application to a Mycobacterial Transcriptional Regulator, ACS Chemical Biology, vol.5, issue.11, pp.1007-1013, 2010.
DOI : 10.1021/cb100177g

P. Grimster, B. Stump, J. R. Fotsing, T. Weide, T. T. Talley et al., Generation of Candidate Ligands for Nicotinic Acetylcholine Receptors via in situ Click Chemistry with a Soluble Acetylcholine Binding Protein Template, Journal of the American Chemical Society, vol.134, issue.15, pp.6732-6740, 2012.
DOI : 10.1021/ja3001858

E. Ronco, J. Carletti, M. Colletier, F. Weik, L. Nachon et al., Huprine Derivatives as Sub-Nanomolar Human Acetylcholinesterase Inhibitors: From Rational Design to Validation by X-ray Crystallography, ChemMedChem, vol.51, issue.3, pp.400-405, 1999.
DOI : 10.1002/cmdc.201100438

URL : https://hal.archives-ouvertes.fr/hal-00996475

Y. Senapati, J. A. Cheng, and . Mccammon, In-situ Synthesis of a Tacrine-Triazole-Based Inhibitor of Acetylcholinesterase:?? Configurational Selection Imposed by Steric Interactions, Journal of Medicinal Chemistry, vol.49, issue.21, pp.6222-6230, 2006.
DOI : 10.1021/jm051132b

J. , T. , J. ¼. , T. , J. ¼1h et al., 13 C NMR (100 MHz, 6.9 Hz), 3.88 (3H, s, CH 3 O), 5.14 (2H, s, PhCH 2 O), 7.18e7.38, pp.4964-4967, 1993.

2. , T. , J. ¼2h, T. , and J. ¼. , Hz) 13 C NMR (100 MHz, CDCl 3 , d): 20, H NMR (300 MHz 7.2 Hz), 4.00 (3H, s, CH 3 O), 7.23 (1H, d, J ¼ 8.6 Hz)41) Compound 41 was obtained by the general procedure 4 from 38 with yield 37% (over three steps). R f ¼ 0, pp.1-40, 2006.

1. , D. , J. ¼1h, J. ¼. Td, and J. ¼. Td, 13 C NMR (100 MHz, Hz, J ¼ 1 Hz), 7.89e7.93 (2H, m), 9.98 (1H, s, pp.31-38

. Paraoxon and . Sigmaealdrich, Stock solution of VX and tabun were 5 mM in isopropanol. The inhibition of 120 mM hAChE is realized with a 5-fold excess of OPs and was performed in tris buffer (20 mM, pH 7.4, 0.1% BSA) at 25 C. After a 20-min incubation

P. Taylor, . Goodman, . E. Gilman-'sb-)-r, and . Langford, The Pharmacological Basis of Therapeutics, p.175, 2001.

F. R. Sidell and J. Borak, Chemical warfare agents: II. nerve agents, Annals of Emergency Medicine, vol.21, issue.7, pp.865-871, 1992.
DOI : 10.1016/S0196-0644(05)81036-4

M. Eddleston, N. A. Buckley, P. Eyer, and A. H. Dawson, Management of acute organophosphorus pesticide poisoning, The Lancet, vol.371, issue.9612, pp.597-607, 2008.
DOI : 10.1016/S0140-6736(07)61202-1

M. Eddleston, L. Karalliedde, N. Buckley, R. Fernando, G. Hutchinson et al., Pesticide poisoning in the developing world???a minimum pesticides list, The Lancet, vol.360, issue.9340, pp.1163-1167, 2002.
DOI : 10.1016/S0140-6736(02)11204-9

G. Mercey, T. Verdelet, J. Renou, M. Kliachyna, R. Baati et al., Reactivators of Acetylcholinesterase Inhibited by Organophosphorus Nerve Agents, Accounts of Chemical Research, vol.45, issue.5, pp.756-766, 2012.
DOI : 10.1021/ar2002864

URL : https://hal.archives-ouvertes.fr/hal-01015972

D. E. Lorke, H. Kalasz, G. A. Petroianu, and K. Tekes, Entry of Oximes into the Brain: A Review, Current Medicinal Chemistry, vol.15, issue.8, pp.743-753, 2008.
DOI : 10.2174/092986708783955563

T. M. Shih, J. W. Skovira, J. C. O-'donnell, and J. H. Mcdonough, Central acetylcholinesterase reactivation by oximes improves survival and terminates seizures following nerve agent intoxication, Advanced Studies in Biology, vol.1, pp.155-196, 2009.
DOI : 10.1007/s12031-009-9259-7

M. C. De-koning, M. Van-grol, and D. Noort, Peripheral site ligand conjugation to a non-quaternary oxime enhances reactivation of nerve agent-inhibited human acetylcholinesterase, Toxicology Letters, vol.206, issue.1, pp.54-59, 2011.
DOI : 10.1016/j.toxlet.2011.04.004

C. , R. K. Sit, Z. Kovarik, S. Berend, E. Garcia et al., Refinement of structural leads for centrally acting oxime reactivators of phosphylated cholinesterases, New structural scaffolds for centrally acting oxime reactivators of phosphylated cholinesterases, 2011.

J. Kalisiak, E. C. Ralph, J. Zhang, J. R. Cashman, ). J. Kalisiak et al., Amidine-oximes: reactivators for organophosphate exposure Nonquaternary reactivators for organophosphate-inhibited cholinesterases, Journal of Medicinal Chemistry Journal of Medicinal Chemistry, vol.54, issue.55, pp.465-474, 2011.

W. P. Jencks and J. Carriuolo, Reactivity of Nucleophilic Reagents toward Esters, Journal of the American Chemical Society, vol.82, issue.7, pp.1778-1786, 1960.
DOI : 10.1021/ja01492a058

G. Saint-andré, M. Kliachyna, S. Kodepelly, L. Louise-leriche, E. Gillon et al., Design, synthesis and evaluation of new ??-nucleophiles for the hydrolysis of??organophosphorus nerve agents: application to the reactivation of??phosphorylated acetylcholinesterase, Tetrahedron, vol.67, issue.34, pp.6352-6361, 2011.
DOI : 10.1016/j.tet.2011.05.130

L. Louise-leriche, E. , G. Saint-andré, R. Baati, A. Romieu et al., A HTS Assay for the Detection of Organophosphorus Nerve Agent Scavengers, Chemistry - A European Journal, vol.70, issue.158, 2010.
DOI : 10.1002/chem.200902986

URL : https://hal.archives-ouvertes.fr/hal-00991892

A. Krasi-nski, Z. Radi-c, R. Manetsch, J. Raushel, P. Taylor et al., In Situ Selection of Lead Compounds by Click Chemistry:?? Target-Guided Optimization of Acetylcholinesterase Inhibitors, Journal of the American Chemical Society, vol.127, issue.18, pp.6686-6692, 2005.
DOI : 10.1021/ja043031t

G. Mercey, T. Verdelet, G. Saint-andré, E. Gillon, A. Wagner et al., First efficient uncharged reactivators for the dephosphylation of poisoned human acetylcholinesterase Phenyltetrahydroisoquinoline-pyridinaldoxime conjugates as efficient uncharged reactivators for the dephosphylation of inhibited human acetylcholinesterase, Tryptoline-3-hydroxypyridinaldoxime conjugates as efficient reactivators of phosphylated human acetyl and butyrylcholinesterases, pp.50-3947, 2011.

Y. Ashani, A. K. Bhattacharjee, H. Leader, A. Saxena, and B. P. Doctor, Inhibition of cholinesterases with cationic phosphonyl oximes highlights distinctive properties of the charged pyridine groups of quaternary oxime reactivators, Biochemical Pharmacology, vol.66, issue.2, p.66, 2003.
DOI : 10.1016/S0006-2952(03)00204-1

J. P. Colletier, B. Sanson, F. Nachon, E. Gabellieri, C. Fattorusso et al., Acetylcholinesterase Revealed by the Complex Structure with a Bifunctional Inhibitor, Journal of the American Chemical Society, vol.128, issue.14, pp.4526-4527, 2006.
DOI : 10.1021/ja058683b

E. H. Rydberg, B. Brumshtein, H. M. Greenblatt, D. M. Wong, D. Shaya et al., Acetylcholinesterase:?? Binding of Bis(5)-tacrine Produces a Dramatic Rearrangement in the Active-Site Gorge, Journal of Medicinal Chemistry, vol.49, issue.18, pp.5491-5500, 2006.
DOI : 10.1021/jm060164b

J. L. Sussman, M. Harel, F. Frolow, C. Oefner, A. Goldman et al., Atomic structure of acetylcholinesterase from Torpedo californica: a prototypic acetylcholine-binding protein, Science, vol.253, issue.5022, 1991.
DOI : 10.1126/science.1678899

J. P. Colletier, D. Fournier, H. M. Greenblatt, J. Stojan, J. L. Sussman et al., Structural insights into substrate traffic and inhibition in acetylcholinesterase, The EMBO Journal, vol.172, issue.12, pp.25-2746, 2006.
DOI : 10.1016/0006-3002(51)90066-2

URL : https://hal.archives-ouvertes.fr/hal-00120647

Y. Bourne, P. Taylor, Z. Radic, and P. Marchot, Structural insights into ligand interactions at the acetylcholinesterase peripheral anionic site, The EMBO Journal, vol.22, issue.1, pp.22-23, 2003.
DOI : 10.1093/emboj/cdg005

Y. Bourne, H. C. Kolb, Z. Radic, K. B. Sharpless, P. Taylor et al., Freeze-frame inhibitor captures acetylcholinesterase in a unique conformation, Proceedings of the National Academy of Sciences, vol.101, issue.6, pp.1449-1454, 2004.
DOI : 10.1073/pnas.0308206100

W. G. Lewis, L. G. Green, F. Grynszpan, Z. Radic, P. R. Carlier et al., Click Chemistry In Situ: Acetylcholinesterase as a Reaction Vessel for the Selective Assembly of a Femtomolar Inhibitor from an Array of Building Blocks, Angewandte Chemie International Edition, vol.274, issue.6, pp.1053-1057, 2002.
DOI : 10.1002/1521-3773(20020315)41:6<1053::AID-ANIE1053>3.0.CO;2-4

S. Butini, G. Campiani, M. Borriello, S. Gemma, A. Panico et al., Exploiting Protein Fluctuations at the Active-Site Gorge of Human Cholinesterases: Further Optimization of the Design Strategy to Develop Extremely Potent Inhibitors, Journal of Medicinal Chemistry, vol.51, issue.11, pp.3154-3170, 2008.
DOI : 10.1021/jm701253t

C. Ronco, L. Jean, H. Outaabout, and P. Renard, Palladium-Catalyzed Preparation of N-Alkylated Tacrine and Huprine Compounds, European Journal of Organic Chemistry, vol.66, issue.2, pp.302-310, 2011.
DOI : 10.1002/ejoc.201001158

URL : https://hal.archives-ouvertes.fr/hal-01017284

T. Verdelet, G. Mercey, N. Correa, L. Jean, and P. Renard, Straightforward and efficient synthesis of 3-benzyloxy-4-bromopicolinate ester and 3-benzyloxy-5-bromopicolinate ester, common building blocks for pharmaceuticals and agrochemicals, Tetrahedron, vol.67, issue.45, 2011.
DOI : 10.1016/j.tet.2011.09.024

URL : https://hal.archives-ouvertes.fr/hal-01017528

R. Manetsch, A. Krasi-nski, Z. Radi-c, J. Raushel, P. Taylor et al., In Situ Click Chemistry:?? Enzyme Inhibitors Made to Their Own Specifications, Journal of the American Chemical Society, vol.126, issue.40, pp.12809-12818, 2004.
DOI : 10.1021/ja046382g

F. Worek, H. Thiermann, L. Szinicz, and P. Eyer, Kinetic analysis of interactions between human acetylcholinesterase, structurally different organophosphorus compounds and oximes, Biochemical Pharmacology, vol.68, issue.11, 2004.
DOI : 10.1016/j.bcp.2004.07.038

F. Worek, T. Wille, M. Koller, and H. Thiermann, Reactivation kinetics of a series of related bispyridinium oximes with organophosphate-inhibited human acetylcholinesterase???Structure???activity relationships, Biochemical Pharmacology, vol.83, issue.12, pp.1700-1706, 2012.
DOI : 10.1016/j.bcp.2012.03.002

Y. Wang, Y. Wei, S. Oguntayo, B. P. Doctor, M. P. Nambiar et al., A combination ofHuperzine A improves protection against soman toxicity compared to [þ]-Huperzine A in guinea pigs Heterodimeric tacrine-based acetylcholinesterase inhibitors: investigating ligand-peripheral site interactions, 2013) 120e124. [36] (a), pp.4657-4666, 1999.

E. Carletti, H. Li, B. Li, F. Ekström, Y. Nicolet et al., Aging of Cholinesterases Phosphylated by Tabun Proceeds through O-Dealkylation, Journal of the American Chemical Society, vol.130, issue.47, pp.16011-16020, 2008.
DOI : 10.1021/ja804941z

B. Hess, C. Kutzner, D. Van-der-spoel, and E. , GROMACS 4:?? Algorithms for Highly Efficient, Load-Balanced, and Scalable Molecular Simulation, Journal of Chemical Theory and Computation, vol.4, issue.3, pp.435-447, 2008.
DOI : 10.1021/ct700301q

V. Hornak, R. Abel, A. Okur, B. Strockbine, A. Roitberg et al., Comparison of multiple Amber force fields and development of improved protein backbone parameters, Proteins: Structure, Function, and Bioinformatics, vol.43, issue.3, pp.712-725, 2006.
DOI : 10.1002/prot.21123

J. Wang, R. M. Wolf, J. W. Caldwell, P. A. Kollman, and D. A. Case, Development and testing of a general amber force field, Journal of Computational Chemistry, vol.17, issue.9, pp.1157-1174, 2004.
DOI : 10.1002/jcc.20035

H. J. Berendsen, J. P. Postma, W. F. Van-gunsteren, A. Dinola, and J. R. Haak, Molecular dynamics with coupling to an external bath, The Journal of Chemical Physics, vol.81, issue.8, pp.3684-3690, 1984.
DOI : 10.1063/1.448118

B. Hess, H. Bekker, H. J. Berendsen, and J. G. Fraaije, LINCS: A linear constraint solver for molecular simulations, Journal of Computational Chemistry, vol.19, issue.12, pp.1463-1472, 1997.
DOI : 10.1002/(SICI)1096-987X(199709)18:12<1463::AID-JCC4>3.0.CO;2-H

C. Winder, C. R. Mackerer, M. L. Barth, A. J. Krueger, B. Chawla et al., Air monitoring studies for aircraft cabin contamination Comparison of neurotoxic effects and potential risks from oral administration or ingestion of tricresyl phosphate and jet engine oil containing tricresyl phosphate Exposure to tri-o-cresyl phosphate detected in jet airplane passengers Biological activity of a trio-cresyl phosphate metabolite Hydroxylation and cyclization reactions involved in the metabolism of tri-o-cresyl phosphate Plasma albumin as a catalyst in cyclization of diaryl o-(alpha-hydroxy)tolyl phosphates Reaction of cresyl saligenin phosphate, the organophosphorus agent implicated in aerotoxic syndrome, with human cholinesterases: mechanistic studies employing kinetics, mass spectrometry, and X-ray structure analysis Evolution of and perspectives on therapeutic approaches to nerve agent poisoning, 293?328. (3) 1396?1397. (5) Eto, Kinetic analysis of interactions between human acetylcholinesterase, structurally different organophosphorus compounds and oximes, pp.337-347, 1961.

M. Harel, I. Schalk, L. Ehret-sabatier, F. Bouet, M. Goeldner et al., Quaternary ligand binding to aromatic residues in the active-site gorge of acetylcholinesterase Structural study of the complex stereoselectivity of human butyrylcholinesterase for the neurotoxic V-agents The toxicity of commercial jet oils Aircraft air quality incidents: symptoms, exposures and possible solutions Structure-activity relationships for substrates and inhibitors of hen brain neurotoxic esterase Neuropathy target esterase, Proc. Natl. Acad. Sci. U.S.A. 90, 9031?9035. (11) Wandhammer, 16783?16789. (12) 146?164. (13) van Netten, pp.460-468, 1954.

C. J. Earl, R. H. Thompson, L. M. Schopfer, C. E. Furlong, O. Lockridge et al., Development of diagnostics in the search for an explanation of aerotoxic syndrome Engineering of a monomeric and low-glycosylated form of human butyrylcholinesterase: expression, purification, characterization and crystallization Aging of cholinesterases phosphylated by tabun proceeds through O-dealkylation Huprine derivatives as subnanomolar human acetylcholinesterase inhibitors: from rational design to validation by X-ray crystallography A decade of user operation on the macromolecular crystallography MAD beamline ID14?4 at the ESRF MOLREP: an automated program for molecular replacement The CCP4 suite: programs for protein crystallography Refinement of macromolecular structures by the maximum-likelihood method Features and development of Coot, Br. J. Pharmacol. Chemother. 7, 261?269. (18) 630?637. (20) ChemMedChem 6, 876?888. (22) 803?812. (23) Kabsch, W. (2010) XDS. Acta Crystallogr., Sect. D 66, 125?132. (24) 1022? 1025. (25) Collaborative-Computational-Project-4, pp.760-763, 1952.

H. Pettersen, E. F. Goddard, T. D. Huang, C. C. Couch, G. S. Greenblatt et al., PHENIX: a comprehensive Python-based system for macromolecular structure solution UCSF Chimera: a visualization system for exploratory research and analysis, Acta Crystallogr., Sect. D J. Comput. Chem, vol.66, issue.2530, pp.213-221, 2004.

S. Hornak, V. Abel, R. Okur, A. Strockbine, B. Roitberg et al., Comparison of multiple Amber force fields and development of improved protein backbone parameters Development and testing of a general amber force field Automatic atom type and bond type perception in molecular mechanical calculations GROMACS 4: algorithms for highly efficient, load-balanced, and scalable molecular simulation A five-site model for liquid water and the reproduction of the density anomaly by rigid, nonpolarizable potential functions Particle mesh Ewald: an N.Log(N) method for Ewald sums in large systems, Nucleic Acids Res. 39, W511?517. (31) 247?260. (34) 435?447. (35), pp.712-725, 1993.

P. Humphrey, W. Dalke, A. Schulten, K. Bourne, Y. Taylor et al., Crystal structure of mouse acetylcholinesterase. A peripheral site- Chemical Research in Toxicology Article dx.doi.org/10 280?289 occluding loop in a tetrameric assembly Induced-fit or preexisting equilibrium dynamics? Lessons from protein crystallography and MD simulations on acetylcholinesterase and implications for structure-based drug design Structures of human acetylcholinesterase in complex with pharmacologically important ligands A step toward the reactivation of aged cholinesterases -Crystal structure of ligands binding to aged human butyrylcholinesterase Crystal structures of oxime-bound fenamiphosacetylcholinesterases: reactivation involving flipping of the His447 ring to form a reactive Glu334-His447-oxime triad Complexes of alkylene-linked tacrine dimers with Torpedo californica acetylcholinesterase: Binding of Bis5-tacrine produces a dramatic rearrangement in the active-site gorge, 10282?10286. (41) Wandhammer, pp.601-605, 1021.

C. Xu, Y. Colletier, J. P. Weik, M. Jiang, H. Moult et al., Flexibility of aromatic residues in the activesite gorge of acetylcholinesterase: X-ray versus molecular dynamics Conversion of acetylcholinesterase to butyrylcholinesterase: modeling and mutagenesis, 2500?2511. (45) Proc. Natl. Acad, 1992.

. U. Sci, A. Ordentlich, D. Barak, C. Kronman, Y. Flashner et al., Dissection of the human acetylcholinesterase active center determinants of substrate specificity. Identification of residues constituting the anionic site, the hydrophobic site, and the acyl pocket, J. Biol. Chem. Chem.-Biol, vol.89, issue.268, pp.10827-10831, 1993.

I. Nachon, F. Carletti, E. Worek, F. Masson, and P. , Aging mechanism of butyrylcholinesterase inhibited by an N-methyl analogue of tabun: Implications of the trigonal???bipyramidal transition state rearrangement for the phosphylation or reactivation of cholinesterases, 44?48. Chemical Research in Toxicology Article dx.doi.org/10.1021/tx3004505, pp.157-162, 2010.
DOI : 10.1016/j.cbi.2010.03.053