A fluorine scan of thrombin inhibitors to map the fluorophilicity/fluorophobicity of an enzyme active site: Evidence for C-F⋯C=O interactions

Angewandte Chemie - International Edition

Volumn 42, Issue 22, 2003, Pages 2507-2511

  Olsen, Jacob A ^b   Banner, David W ^a   Seiler, Paul ^b   Sander, Ulrike Obst ^a   D'Arcy, Allan ^a   Stihle, Martine ^a   Müller, Klaus ^a   Diederich, François ^b  

^a F HOFFMANN LA ROCHE LTD   (Switzerland)

^b ETH ZURICH   (Switzerland)

Author keywords

Fluorine; Inhibitors; Medicinal chemistry; Molecular recognition; Structure elucidation; Thrombin

Indexed keywords

CHEMICAL BONDS; COMPLEXATION; CRYSTAL STRUCTURE; FLUORINE; X RAY CRYSTALLOGRAPHY;

THROMBIN INHIBITORS;

ENZYMES;

BENZYL DERIVATIVE; CARBONYL DERIVATIVE; ENZYME; FLUORINE DERIVATIVE; ORGANOFLUORINE DERIVATIVE; THROMBIN; THROMBIN INHIBITOR; TRYPSIN;

ARTICLE; BINDING AFFINITY; BLOOD CLOTTING; CRYSTAL STRUCTURE; ENZYME ACTIVE SITE; FLUORESCENCE; FLUORINATION; FLUOROPHILICITY; FLUOROPHOBICITY; GEOMETRY; MOLECULAR INTERACTION; PROTEIN INTERACTION; STEREOCHEMISTRY; X RAY CRYSTALLOGRAPHY;

BINDING SITES; CRYSTALLOGRAPHY, X-RAY; FLUORINE; LIGANDS; MODELS, MOLECULAR; MOLECULAR STRUCTURE; SERINE PROTEINASE INHIBITORS; STEREOISOMERISM; THROMBIN; TRYPSIN;

EID: 0037663879     PISSN: 14337851     EISSN: None     Source Type: Journal    
DOI: 10.1002/anie.200351268     Document Type: Article

References (37)

1. a) K. Park, N.R. Kitteringham, P.M. O'Neill, Annu. Rev. Pharmacol. Toxicol. 2001, 41, 443-470;
2. b) D. O'Hagan, H. S. Rzepa, Chem. Commun. 1997, 645-652;
3. c) B.E. Smart, J. Fluorine Chem. 2001, 109, 3-11.
4. M. Schlosser, D. Michel, Tetrahedron 1996, 52, 99-108.
5. J. Hernández-Trujillo, A. Vela, J. Phys. Chem. 1996, 100, 6524-6530.
6. For a review, see E. A. Meyer, R. K. Castellano, E Diederich, Angew. Chem. 2003, 115, 1244-1287, Angew. Chem. Int. Ed. 2003, 42, 1210-1250.
7. For a review, see E. A. Meyer, R. K. Castellano, E Diederich, Angew. Chem. 2003, 115, 1244-1287, Angew. Chem. Int. Ed. 2003, 42, 1210-1250.
8. J.A. Ippolito, D. W. Christianson, Int. J. Biol. Macromol. 1992, 14, 193-197.
9. B. C. Finzel, E.T. Baldwin, G.L. Bryant, Jr., G. F. Hess, J. W. Wilks, C. M. Trepod, J. E. Mort, V. P. Marshall, G. L. Petzold, R. A. Poorman, T. J. O'Sullivan, H. J. Schostarez, M. A. Mitchell, Protein Sci. 1998, 7, 2118-2126.
10. a) C.-Y Kim, J.S. Chang, J.B. Doyon, T.A. Baird, Jr., C.A. Fierke, A. Jain, D. W. Christianson, J. Am. Chem. Soc. 2000, 122, 12125-12134;
11. b) R. D. Madder, C.-Y. Kim, P. P. Chandra, J. B. Doyon, T. A. Baird, Jr., C. A. Fierke, D. W. Christianson, J. G. Voet, A. Jain, J. Org. Chem. 2002, 67, 582- 584.
12. A. Kashima, Y. Inoue, S. Sugio, I. Maeda, T. Nose, Y. Shimohigashi, Eur. J. Biochem. 1998, 255, 12-23.
13. F. T. T. Huque, K. Jones, R. A. Saunders, J. A. Platts, J. Fluorine Chem. 2002, 115, 119-128.
14. a) U. Obst, V. Gramlich, F. Diederich, L. Weber, D. W. Banner, Angew. Chem. 1995, 107, 1874-1877; Angew. Chem. Int. Ed. Engl. 1995, 34, 1739-1742;
15. a) U. Obst, V. Gramlich, F. Diederich, L. Weber, D. W. Banner, Angew. Chem. 1995, 107, 1874-1877; Angew. Chem. Int. Ed. Engl. 1995, 34, 1739-1742;
16. b) U. Obst, D. W. Banner, L. Weber, F. Diederich, Chem. Biol. 1997, 4, 287-295;
17. c) U. Obst, P. Betschmann, C. Lerner, P. Sieler, F. Diederich, V. Gramlich, L. Weber, D. W. Banner, P. Schönholzer, Helv. Chim. Acta 2000, 83, 855-909;
18. d) P. Betschmann, S. Sahli, F. Diederich, U. Obst, V. Gramlich, Helv. Chim. Acta 2002, 85, 1210-1245.
19. For recent examples of other thrombin inhibitors, see a) J. Z. Ho, T. S. Gibson, J. E. Semple, Bioorg. Med. Chem. Lett. 2002, 12, 743-748;
20. b) S. Hanessian, E. Therrien, K. Granberg, I. Nilsson, Bioorg. Med. Chem. Lett. 2002, 12, 2907-2911;
21. c) for a review, see J. B. M. Rewinkel, A. E. P. Adang, Curr. Pharm. Des. 1999, 5, 1043-1075.
22. The term fluorine scan has been coined in a recent report on a computational fluorine scan of biotin, see B. Kuhn, P.A. Kollman, J. Am. Chem. Soc. 2000, 122, 3909-3916.
23. 13C NMR spectroscopy, MS, and HR-MS or elemental analysis.
24. K. Hilpert, J. Ackermann, D. W. Banner, A. Gast, K. Gubernatot, P. Hadváry, L. Labler, K. Müller, G. Schmid, T. B. Tschopp, H. van de Waterbeemd, J. Med. Chem. 1994, 37, 3889-3901.
25. 2. PDB, code: 10YT.
26. 2. PDB, code: 10YT.
27. a) P. R. Gerber, K. Müller, J. Comput.-Aided Mater. Des. 1995, 9, 251-268;
28. α atom of Asn98 is based on stereochemical consideration with a C⋯H distance of 1.08 Å.
29. R. Vargas, J. Garza, D. A. Dixon, B. P. Hay, J. Am. Chem. Soc. 2000, 122, 4750-4755.
30. V. R. Thalladi, H.-C. Weiss, D. Bläser, R. Boese, A. Nangia, G. R. Desiraju, J. Am. Chem. Soc. 1998, 120, 8702-8710.
31. J. Parsch, J. W. Engels, J. Am. Chem. Soc. 2002, 124, 5664-5672.
32. J. D. Dunitz, R. Taylor, Chem. Eur. J. 1997, 3, 89-98.
33. A. Matsushima, T. Fujita, T. Nose, Y. Shimohigashi, J. Biochem. 2000, 128, 225-232.
34. CCDC 203566-203568 ((±)-10-(±)-12) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB21EZ, UK; fax: (+44) 1223-336-033; or deposit@ccdc.cam.ac.uk). Further details are found as Supporting Information.
35. The H positions are based on stereochemical consideration with a C⋯H distance of 1.08 Å.
36. CSD Version 5.24, November 2002, which holds over 270000 small-molecule crystal structures.
37. The F⋯C=O interaction bears some structural resemblance to the interaction of nucleophiles with the carbonyl groups investigated: B. Bürgi, J. D. Dunitz, Acc. Chem. Res. 1983, 16, 153161.