Automated docking with protein flexibility in the design of femtomolar "click Chemistry" inhibitors of acetylcholinesterase

Journal of Chemical Information and Modeling

Volumn 53, Issue 4, 2013, Pages 898-906

  Morris, Garrett M ^a   Green, Luke G ^b   Radić, Zoran ^d   Taylor, Palmer ^d   Sharpless, K Barry ^b   Olson, Arthur J ^b   Grynszpan, Flavio ^c  

^a Cherwell Innovation Center   (United Kingdom)

^b SCRIPPS RESEARCH INSTITUTE   (United States)

^c ARIEL UNIVERSITY   (Israel)

^d UNIVERSITY OF CALIFORNIA SAN DIEGO   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

APPLICATION PROGRAMS; CHELATION; LIGANDS; PROTEINS; SYNTHESIS (CHEMICAL);

ACETYLCHOLINESTERASE; AUTOMATED DOCKING; CONFORMATIONAL FLEXIBILITY; FLEXIBLE LIGANDS; NONCOVALENT INHIBITORS; PROTEIN FLEXIBILITY; STRUCTURE BASED DRUG DESIGNS; TARGET PROTEINS;

CONFORMATIONS;

ACETYLCHOLINESTERASE; CHOLINESTERASE INHIBITOR; LIGAND;

ARTICLE; BINDING SITE; CHEMISTRY; CLICK CHEMISTRY; COMPUTER AIDED DESIGN; COMPUTER PROGRAM; DRUG DESIGN; HUMAN; MOLECULAR DOCKING; MOLECULAR LIBRARY; PROTEIN BINDING; PROTEIN DOMAIN;

ACETYLCHOLINESTERASE; BINDING SITES; CHOLINESTERASE INHIBITORS; CLICK CHEMISTRY; COMPUTER-AIDED DESIGN; DRUG DESIGN; HUMANS; LIGANDS; MOLECULAR DOCKING SIMULATION; PROTEIN BINDING; PROTEIN INTERACTION DOMAINS AND MOTIFS; SMALL MOLECULE LIBRARIES; SOFTWARE;

EID: 84876587110     PISSN: 15499596     EISSN: 1549960X     Source Type: Journal    
DOI: 10.1021/ci300545a     Document Type: Article

References (41)

1. Matter, H.; Baringhaus, K. H.; Naumann, T.; Klabunde, T.; Pirard, B. Computational approaches towards the rational design of drug-like compound libraries Comb. Chem. High Throughput Screening 2001, 4, 453-457
2. Mezey, P. G. Computer aided drug design: some fundamental aspects J. Mol. Model. 2000, 6, 150-157
3. Drews, J. Drug discovery: a historical perspective Science 2000, 287, 1960-1963
4. Wess, G.; Urman, M.; Sickenberger, B. Medicinal chemistry: challenges and opportunities Angew. Chem., Int. Ed. 2001, 40, 3341-3350
5. Morris, G. M.; Goodsell, D. S.; Halliday, R. S.; Huey, R.; Hart, W. E.; Belew, R. K.; Olson, A. J. Automated docking using a Lamarckian genetic algorithm and and empirical binding free energy function J. Comput. Chem. 1998, 19, 1639-1662
6. Lewis, W. G.; Green, L. G.; Grynszpan, F.; Radić, Z.; Carlier, P. R.; Taylor, P.; Finn, M. G.; Sharpless, K. B. Click chemistry in situ: acetylcholinesterase as a reaction vessel for the selective assembly of a femtomolar inhibitor from an array of building blocks Angew. Chem., Int. Ed. 2002, 114, 1095-1099
7. Mamidyala, S. K.; Finn, M. G. In situ click chemistry: probing the binding landscapes of biological molecules Chem. Soc. Rev. 2010, 39, 1252-1261
8. Kirby, A. J. Effective molarities for intramolecular reactions Adv. Phys. Org. Chem. 1980, 17, 183-278
9. Jencks, W. P. On the attribution and additivity of binding energies Proc. Natl. Acad. Sci. U.S.A. 1981, 78, 4046-4050
10. Mammen, M.; Choi, S.-K.; Whitesides, G. M. Polyvalent interactions in biological systems: implications for design and use of multivalent ligands and inhibitors Angew. Chem., Int. Ed. 1998, 37, 2755-2794
11. Huisgen, R. Profiles, Pathways, and Dreams; Seeman, J. I., Ed.; American Chemical Society, Washington, DC, 1994.
12. Mock, W. L. Cucurbituril Top. Curr. Chem. 1995, 175, 1-24
13. Chen, J.; Rebek, J., Jr. Selectivity in an encapsulated cycloaddition reaction Org. Lett. 2002, 4, 327-329
14. Kiick, K. L.; Saxon, E.; Tirrell, D. A.; Bertozzi, C. R. Incorporation of azides into recombinant proteins for chemoselective modification by the Staudinger ligation Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 19-24
15. Ramström, O.; Lehn, J.-M. Drug discovery by dynamic combinatorial libraries Nat. Rev. Drug Discovery 2002, 1, 26-36
16. Sussman, J. L.; Harel, M.; Frolow, F.; Oefner, C.; Goldman, A.; Toker, L.; Silman, I. Atomic structure of acetylcholinesterase from torpedo californica: a prototypic acetylcholine-binding protein Science 1991, 253, 872-879
17. Radić, Z.; Taylor, P. Interaction kinetics of reversible inhibitors and substrates with acetylcholinesterase and its fasciculin 2 complex J. Biol. Chem. 2001, 7, 4622-4633
18. Carlier, P. R.; Han, Y. F.; Chow, E. S.-H.; Li, C. P.-L.; Wang, H.-S.; Lieu, T. X.; Wong, H. S.; Pang, Y.-P. Evaluation of short-tether bis-THA AChE inhibitors. A further test of the dual binding site hypothesis Bioorg. Med. Chem. 1999, 7, 351-357
19. Lappi, S.; Taylor, P. Interaction of fluorescence probes with acetylcholinesterase. Site and specificity of propidium binding Biochemistry 1975, 14, 1989-1997
20. Purchased from Sigma.
21. Bourne, Y.; Grassi, J.; Bourgis, P. E.; Marchot, P. Conformational flexibility of the acetylcholinesterase tetramer suggested by X-ray crystallography J. Biol. Chem. 1999, 274, 30370-30376
22. Sussman, J. L.; Silman, I.; Axelsen, P. H.; Hirth, C.; Goeldner, M.; Bouet, F.; Ehret-Sabatier, L.; Schalk, I.; Harel, M. Quaternary ligand binding to aromatic residues in the active-site gorge of acetylcholinesterase Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 9031-9035
23. When AutoDock 3.0's new force field was created, we introduced constant energy penalties to the oxygen and polar hydrogen maps designed to penalize any hydrogen bonds not formed upon binding. This was based on the assumption that a small molecule when it is unbound is fully hydrated and all possible hydrogen bonds are satisfied. However, when a very large molecule such as a protein is used as the 'ligand', as in protein-protein docking (Ollman-Saffire, E.; Parren, P. W. H. I.; Pantophlet, R.; Zwick, M. B.; Morris, G. M.; Rudd, P. M.; Dwek, R. A.; Stanfield, R. L.; Burton, D. R.; Wilson, I. A. Science 2001, 293, 1155-1159
24. Legge, G. B.; Morris, G. M.; Sanner, M. F.; Takada, Y.; Olson, A. J.; Grynszpan, F. Proteins: Structure, Func., Genetics 2002, 48, 151-160), it is necessary to set these AutoGrid map constants to zero. This is because the assumption breaks down within the protein: no internal hydrogen bonds are lost upon binding within the rigid protein core. If this is not done, the significant number of oxygens and polar hydrogens within the protein generate a large energy penalty, which although constant during the docking, precludes final dockings with negative energies
25. Lavie, A.; Ostermann, N.; Brundiers, R.; Goody, R. S.; Reinstein, J.; Konrad, M.; Schlichting, I. Structural basis for efficient phosphorylation of 3′-azidothymidine monophosphate by Escherichia coli thymidylate kinase Proc. Natl. Acad. Sci. USA. 1998, 95, 14045-14050
26. The partial charges for the azide group were calculated by Dr. Fahmi Himo and Prof. Lou Noodleman, The Scripps Research Institute, La Jolla, California. Personal communication.
27. Harel, M.; Kryger, G.; Rosenberry, T. L.; Mallender, W. D.; Lewis, T.; Fletcher, R. J.; Guss, J. M.; Silman, I.; Sussman, J. L. Three-dimensional structures of Drosophila melanogaster acetylcholinesterase and of its complexes with two potent inhibitors J. Prot. Sci. 2000, 9, 1063-1072
28. Desai, M. C.; Thadeio, P. F.; Lipinski, C. A.; Liston, D. R.; Spencer, R. W.; Williams, I. H. Physical parameters for brian uptake: optimizing log P, log D and pKa of THA Bioorg. Med. Chem. Lett. 1991, 8, 411-414
29. Ross, S. A.; Pitié, M.; Meunier, B. A straightforward preparation of primary alkyl triflates and their utility in the synthesis of derivatives of ethidium J. Chem. Soc., Perkin Trans. 1 2000, 571-574
30. Wei, J.; Buriak, J.; Siuzdak, G. Desorption-ionization mass spectrometry on porous silicon Nature 1999, 401, 243-246
31. Thomas, J. J.; Shen, Z.; Crowell, J. E.; Finn, M. G.; Siuzdak, G. Desorption/ionization on silicon (DIOS): A diverse mass spectrometry platform for protein characterization Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 4932-4937
32. Shen, Z.; Thomas, J. J.; Averbuj, C.; Broo, K. M.; Engelhard, M.; Crowell, J. E.; Finn, M. G.; Siuzdak, G. Porous silicon as a versatile platform for laser desorption/ionization mass spectrometry Anal. Chem. 2001, 73, 612-619
33. Nair, H. K.; Lee, K.; Quinn, D. M. m-(N,N,N-Trimethylammonio) trifluoroacetophenone: a femtomolar inhibitor of acetylcholinesterase J. Am. Chem. Soc. 1993, 115, 9939-9941
34. Harel, M.; Quinn, D. M.; Nair, H. K. The X-ray structure of a transition state analog complex reveals the molecular origins of the catalytic power and substrate specificity of acetylcholinesterase J. Am. Chem. Soc. 1996, 118, 2340-2346
35. Marchot, P.; Khelif, A.; Ji, Y. H.; Mansuelle, P.; Bougis, P. E. Binding of 125I-fasciculin to rat brain acetylcholinesterase. The complex still binds diisopropyl fluorophosphate J. Biol. Chem. 1993, 268, 12458-12467
36. Duran, R.; Cerveñansky, C.; Dajas, F.; Tipton, K. F. Fasciculin inhibition of acetylcholinesterase is prevented by chemical modification of the enzyme at a peripheral site Biochim. Biophys. Acta 1994, 1201, 381-388
37. Radić, Z.; Duran, R.; Vellom, D. C.; Li, Y.; Cerveñansky, C.; Taylor, P. Site of fasciculin interaction with acetylcholinesterase J. Biol. Chem. 1994, 269, 11233-11239
38. Eastman, J.; Wilson, E. J.; Cerveñansky, C.; Rosenberry, T. L. Fasciculin 2 binds to the peripheral site on acetylcholinesterase and inhibits substrate hydrolysis by slowing a step involving proton transfer during enzyme acylation J. Biol. Chem. 1995, 270, 19694-19701
39. Puu, G.; Koch, M. Comparison of kinetic parameters for acetylthiocholine, soman, ketamine and fasciculin towards acetylcholinesterase in liposomes and in solution Biochem. Pharmacol. 1990, 40, 2209-2214
40. Bourne, Y.; Kolb, H. C.; Radić, Z.; Sharpless, K. B.; Taylor, P.; Marchot, P. Freeze-frame inhibitor captures acetylcholinesterase in a unique conformation Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 1449-1454
41. Bourne, Y.; Radić, Z.; Taylor, P.; Marchot, P. Conformational remodeling of femtomolar inhibitor-acetylcholinesterase complexes in the crystalline state J. Am. Chem. Soc. 2010, 132, 18292-18300