Quantification of cation-π interactions in protein-ligand complexes: Crystal-structure analysis of factor Xa bound to a quaternary ammonium ion ligand

Angewandte Chemie - International Edition

Volumn 44, Issue 28, 2005, Pages 4400-4404

  Schärer, Kaspar ^b   Morgenthaler, Martin ^b   Paulini, Ralph ^b   Obst Sander, Ulrike ^a   Banner, David W ^a   Schlatter, Daniel ^a   Benz, Jörg ^a   Stihle, Martine ^a   Diederich, François ^b  

^a F HOFFMANN LA ROCHE LTD   (Switzerland)

^b ETH ZURICH   (Switzerland)

Author keywords

Cation pi interactions; Factor Xa; Inhibitors; Molecular recognition; Thrombin

Indexed keywords

BINDING ENERGY; DATABASE SYSTEMS; ENTHALPY; POSITIVE IONS; PROTEINS;

AROMATIC BOX; AROMATIC GROUPS; BINDING SITES; CHEMICAL EQUATION;

COMPLEXATION;

BLOOD CLOTTING FACTOR 10A; CATION; ENZYME INHIBITOR; LIGAND; QUATERNARY AMMONIUM DERIVATIVE; THROMBIN;

ARTICLE; BINDING SITE; BIOLOGICAL MODEL; CHEMICAL MODEL; CHEMICAL STRUCTURE; CHEMISTRY; COMPUTER SIMULATION; MACROMOLECULE; METABOLISM; STEREOISOMERISM; SYNTHESIS; X RAY CRYSTALLOGRAPHY;

BINDING SITES; CATIONS; COMPUTER SIMULATION; CRYSTALLOGRAPHY, X-RAY; ENZYME INHIBITORS; FACTOR XA; LIGANDS; MACROMOLECULAR SUBSTANCES; MODELS, BIOLOGICAL; MODELS, CHEMICAL; MODELS, MOLECULAR; MOLECULAR STRUCTURE; QUATERNARY AMMONIUM COMPOUNDS; STEREOISOMERISM; THROMBIN;

EID: 22744448212     PISSN: 14337851     EISSN: None     Source Type: Journal    
DOI: 10.1002/anie.200500883     Document Type: Article

References (43)

1. F. Hof, F. Diederich, Chem. Commun. 2004, 477-480.
2. a) N. Zacharias, D. A. Dougherty, Trends Pharmacol. Sci. 2002, 23, 281-287;
3. b) J. C. Ma, D. A. Dougherty, Chem. Rev. 1997, 97, 1303-1324;
4. c) D. A. Dougherty, Science 1996, 271, 163-168;
5. d) D. A. Dougherty, D. A. Stauffer, Science 1990, 250, 1558-1560.
6. For a recent review, see: E. A. Meyer, R. K. Castellano, F. Diederich, Angew. Chem. 2003, 115, 1244-1287;
7. Angew. Chem. Int. Ed. 2003, 42, 1210-1250.
8. P. Gallivan, D. A. Dougherty, Proc. Natl. Acad. Sci. USA 1999, 96, 9459-9464.
9. Members of this class of inhibitors show nearly identical binding geometries in the structurally well-defined active site of thrombin; see: a) K. Schärer, M. Morgenthaler, P. Seiler, F. Diederich, Helv. Chim. Acta 2004, 87, 2517-2538;
10. b) J. A. Olsen, D. W. Banner, P. Seiler, U. Obst-Sander, A. D'Arcy, M. Stihle, K. Müller, F. Diederich, Angew. Chem. 2003, 115, 2611-2615;
11. Angew. Chem. Int. Ed. 2003, 42, 2507-2511;
12. c) U. Obst, D. W. Banner, L. Weber, F. Diederich, Chem. Biol. 1997, 4, 287-295.
13. a) P. R. Gerber, K. Müller, J. Comput.-Aided Mol. Des. 1995, 9, 252-268;
14. b) Gerber Molecular Design (http://www.moloc.ch).
15. 50 determined graphically from a dose-response curve of the inhibitor.
16. E. W. Davie, K. Fujikawa, W. Kisiel, Biochemistry 1991, 30, 10363-10370.
17. a) U. Obst, P. Betschmann, C. Lerner, P. Seiler, F. Diederich, V. Gramlich, L. Weber, D. W. Banner, P. Schönholzer, Helv. Chim. Acta 2000, 83, 855-909;
18. b) Only the enantiomer ent-1 which has the same absolute configuration required for thrombin binding is bound by Factor Xa. For a study of enantiomerically pure tricyclic thrombin inhibitors, see refs. [5a] and [5c].
19. D. Monnaie, D. Arosio, N. Griffon, T. Rose, A. R. Rezaie, E. Di Cera, Biochemistry 2000, 39, 5349-5354.
20. 2. Diffraction data were measured on a Bruker FR591 X-ray generator, with 0.2 mm focus, run at 50 kV/60 mA and equipped with an Osmic focusing monochromator and an Oxford Cryostream cooler run at 100 K. The Marresearch345 (dtb) image plate detector was placed 110 mm from the crystal and scanned with 0.15 mm pixel size. Exposure times were 600 s for 0.5° frames. Data from 262 frames were processed to 1.62 Å resolution using XDS (W. Kabsch, J. Appl. Crystallogr. 1993, 26, 795-800).
21. 1; unit cell dimensions a = 48.84, b = 71.67, and c = 72.75 Å. For 163433 measured reflections 32725 were independent, R factor 6.1 % (37.4 % in the outermost shell, 1.62-1.71 Å), with completeness 98.7 % (97.1 %) and I/σ 15.5 (4.3). Data reduction used the CCP4 package ("The CCP4 Suite: Programs for Protein Crystallography" Acta Crystallogr. Sect. D 1994, 50, 760-763).
22. 2O molecules. The inhibitor density is very clear. Coordinates have been deposited with the Protein Data Bank, PDB-code: 2bok.
23. For selected crystal structures, see: a) S. Maignan, J.-P. Guilloteau, Y. M. Choi-Sledeski, M. R. Becker, W. R. Ewing, H. W. Pauls, A. P. Spada, V. Mikol, J. Med. Chem. 2003, 46, 685-690 (PDB-codes: 1NFU, 1NFW, 1NFX, 1NFY);
24. b) H. Nishida, Y. Miyazaki, T. Mukaihira, F. Saitoh, M. Fukui, K. Harada, M. Itoh, A. Muraoka, T. Matsusue, A. Okamoto, Y. Hosaka, M. Matsumotu, S. Ohnishi, H. Mochizuki, Chem. Pharm. Bull. 2002, 50, 1187-1194 (PDB-codes: 1IQE, 1IQF, 1IQG, 1IQH, 1IQI, 1IQJ, 1IQK, 1IQL, 1IQM, 1IQN);
25. c) S. Maignan, J.-P. Guilloteau, S. Pouzieux, Y. M. Choi-Sledeski, M. R. Becker, S. I. Klein, W. R. Ewing, H. W. Pauls, A. P. Spada, V. Mikol, J. Med. Chem. 2000, 43, 3226-3232 (PDB-codes: 1F0R, 1F0S, 1EZQ);
26. d) M. Adler, D. D. Davey, G. B. Phillips, S.-H. Kim, J. Jancarik, G. Rumennik, D. R. Light, M. Whitlow, Biochemistry 2000, 39, 12534-12542 (PDB-code 1FJS);
27. e) K. Kamata, H. Kawamoto, T. Honma, T. Iwama, S.-H. Kim, Proc. Natl. Acad. Sci. USA 1998, 95, 6630-6635 (PDB-code: 1XKA);
28. f) H. Brandstetter, A. Kühne, W. Bode, R. Huber, W. von der Saal, K. Wirthensohn, R. A. Engh, J. Biol. Chem. 1996, 271, 29988-29992 (PDB-code: 1FAX);
29. g) A positively charged residue placed in the D-pocket (thrombin) or S4-pocket (Factor Xa) of the enzymes was predicted to increase inhibitor selectivity for Factor Xa over thrombin in a computational GRID/CPCA analysis of the corresponding enzyme active sites. However, in contrast to the results of the computational study, the binding data for (±)-2 suggest that the analogous introduction of uncharged hydrophobic groups leads to selective inhibitors of thrombin rather than Factor Xa; M. A. Kastenholz, M. Pastor, G. Cruciani, T. Fox, J. Med. Chem. 2000, 43, 3033-3044.
30. H. Matter, E. Defossa, U. Heinelt, P.-M. Blohm, D. Schneider, A. Müller, S. Herok, H. Schreuder, A. Liesum, V. Brachvogel, P. Lönze, A. Walser, F. Al-Obeidi, P. Wildgoose, J. Med. Chem. 2002, 45, 2749-2769 (PDB-codes: 1LPG, 1LPK).
31. For the energetics of cation-π interactions, see: a) refs. [2-4];
32. b) D. L. Beene, G. S. Brandt, W. Zhong, N. M. Zacharias, H. A. Lester, D. A. Dougherty, Biochemistry 2002, 41, 10262-10269.
33. a) M. Hendlich, A. Bergner, J. Günther, G. Klebe, J. Mol. Biol. 2003, 326, 607-620;
34. b) J. Günther, A. Bergner, M. Hendlich, G. Klebe, J. Mol. Biol. 2003, 326, 621-636.
35. PDB searches were performed using Relibase 1.2.1 (March 2003). All database entries containing ligands possessing quaternary ammonium ions (263 structures), tertiary (1024 structures), and secondary (1594 structures) amines were retrieved together with their binding sites and examined by visual inspection. Molecular graphics images were produced using the UCSF Chimera package from the Computer Graphics Laboratory, University of California, San Francisco (supported by NIH P41RR-01081). http://www.cgl.ucsf.edu/chimera E. F. Pettersen, T. D. Goddard, C. C. Huang, G. S. Couch, D. M. Greenblatt, E. C. Meng, T. E. Ferrin, J. Comput. Chem. 2004, 25, 1605-1612.
36. J. Min, Y. Zhang, R.-M. Xu, Genes Dev. 2003, 17, 1823-1828. PDB-code: 1PFB.
37. A. Schiefner, J. Breed, L. Bösser, S. Kneipl, J. Gade, G. Holtmann, K. Diederichs, W. Weite, E. Bremer, J. Biol. Chem. 2004, 279, 5588-5596. PDB-code: 1R9Q.
38. S. L. Roderick, W. W. Chan, D. S. Agate, L. R. Olsen, M. W. Vetting, K. R. Rajashankar, D. E. Cohen, Nat. Struct. Biol. 2002, 9, 507-511. PDB-code: 1LN3.
39. A. Lenhart, D. J. Reinert, J. D. Aebi, H. Dehmlow, O. H. Morand, G. E. Schulz, J. Med. Chem. 2003, 46, 2083-2092. PDB-code: 1H37.
40. S. A. Jacobs, S. Khorasanizadeh, Science 2002, 295, 2080-2083. PDB-code: 1KNA.
41. E. Pozharski, M. A. Wilson, A. Hewagama, A. B. Shanafelt, G. Petsko, D. Ringe, J. Mol. Biol. 2004, 337, 691-697. PDB-code: 1Q0Y.
42. P. H. N. Celie, S. E. van Rossum-Fikkert, W. J. van Dijk, K. Brejc, A. B. Smit, T. K. Sixma, Neuron 2004, 41, 907-914. PDB-code: 1UW6.
43. F. H. Allen, Acta Crystallogr. Sect. B 2002, 58, 380-388. The CSD search was performed using a distance constraint for the distance d between ammonium N atom and the centroid of the aromatic ring of 3.5 Å < d < 5.5 Å. Hits were limited to structures containing no errors or partial disorders, excluding polymeric, powder, or organometallic compounds.