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Molecular Recognition at the Active Site of Factor Xa Research Collection Doctoral Thesis Molecular recognition at the active site of factor Xa Author(s): Salonen, Laura Maria Publication Date: 2011 Permanent Link: https://doi.org/10.3929/ethz-a-006882501 Rights / License: In Copyright - Non-Commercial Use Permitted This page was generated automatically upon download from the ETH Zurich Research Collection. For more information please consult the Terms of use. ETH Library Diss. ETH No. 19728 Molecular Recognition at the Active Site of Factor Xa A dissertation submitted to the ETH ZURICH for the degree of DOCTOR OF SCIENCES Presented by Laura Maria Salonen M.Sc., University of Turku, Finland Born December 3rd, 1980 Citizen of Finland Accepted on the recommendation of Prof. Dr. François Diederich, examiner Prof. Dr. Bernhard Jaun, co-examiner Dr. Wolfgang Haap, co-examiner Zürich 2011 Vanhemmilleni Acknowledgements First, I would like to thank Prof. Dr. François Diederich for giving me the opportunity to work in his group on this exciting project. I really appreciate the freedom, the possibilities, the support, and the encouragement he gave me during my thesis. I especially want to thank him for giving me the chance to write a review: this was an immense learning experience for me, and very rewarding. I would like to thank Prof. Dr. Bernhard Jaun for accepting to be my co-examiner, and for his help in NMR analysis. Dr. Wolfgang Haap was always extremely helpful in all factor Xa-related questions. I would also like to thank him for all his support prior to and during this thesis, and for accepting to be my co-examiner. I would like to thank Dr. David W. Banner for the X-ray cocrystal structures, which contributed greatly to this work. I especially appreciate his enthusiasm during the many helpful discussions on this project. For enabling the biological measurements performed during this work, I would like to thank Dr. Jacques Himber and Jean-Luc Mary. A special thanks goes to Olivier Kuster for advice and for teaching me how to perform the assays. I would like to thank David Wechsler and Daniel Zimmerli for their great help in LC- MS-related questions and for the enantiomeric resolutions. I would like to thank all staff members of the LOC for the valuable services, in particular: the MS service: Dr. Walter Amrein, Dr. Xiangyang Zhang, Louis Bertschi, Oswald Greter, and Rolf Häfliger for measuring the mass spectra; the NMR service: Prof. Dr. Bernhard Jaun, Dr. Marc-Olivier Ebert, Rainer Frankenstein, and Philipp Zumbrunnen for their help and recording the NMR spectra; the Micro-Laboratory for the elemental analyses; Dr. W. Bernd Schweizer and Paul Seiler for X-ray structure analysis; Thomas Mäder for his great help and support in all HPLC-related problems. Many thanks to Irma Näf for her help in all administrative issues, her kindness, and support. I would like to thank Prof. Dr. Carlo Thilgen for his administrative help and advice on the student projects. I would like to thank Dr. Bruno Bernet for correcting the experimental part and his advice in all questions related to it. I would like to thank Pablo Rivera Fuentes for performing the calculations presented in this thesis. For their patient help in all computer problems I encountered, I would like to thank Dr. Christoph Fäh, Dr. Christian Eberle, Luzi Barandun, Andri Schütz, and Daniel Fankhauser. The students Christoph Bucher, Mareike Holland, Philip Kaib, Sandra Kienast, Moritz Hunkeler, and Matthias Knecht, who I had the opportunity to work with, I would like to thank for contributions to this work and for creating a nice working atmosphere in the lab. I would like to thank Paolo Mombelli, Petra Fesser, Dr. Lorenzo Alonso Gómez, Dr. Matthias Vogt, Dr. Nicolas Marion, and Jesse Roose for their great help in correcting this thesis in record time. I greatly appreciate all the discussions with Leo Hardegger and Paolo on my project, their projects, and any noncovalent interaction. I would like to thank Nicolas and Paolo for their constant encouragement during coffee breaks, which never failed to make me feel that the goals that I set were reachable. Working in G320 was a lot of fun! To the great atmosphere contributed Paolo, Julie Geist, Dr. Manuel Ellermann, Dr. Markus Jordan, Dr. Thomas Gottschalk, and Dr. Hai Xu. Thanks for all the people that made my long-ish stay in G327 much more pleasant: Manuel, Dr. Philipp Kohler, Dr. Kara Howes, Michael Harder, Haraldur Gardarsson, Boris Tchitchanov, Dr. Valentina Aureggi, and Julie. I thank the Spanish–German lunch group, Lorenzo, Dr. Henry Dube, Dr. Martina Zürcher, Petra, Pablo, Kara, and Manuel, for making the lunch breaks a lot of fun, sometimes even educational. I would like to thank the usual suspects for many great, late evenings! Many people in the DCC have made the time in the group, both at and after work, so enjoyable! Many thanks to Petra, Paolo, Lorenzo, Nicolas, Pablo, Kara, Dr. Anthoni van Zijl, Henry, Dr. Bernhard Stump, Leo, Julie, Manuel, Michael H., Halli, Markus, Dr. Fabio Silvestri, Jesse, Dr. Tobias Voigt, Veronika Ehmke, Sophie Müller, Benjamin Breiten, Michael Seet, Luzi, Dr. Anna Hirsch, Dr. Anna Vogt, Dr. Simone Hörtner, Martina, Dr. Agnieszka Kraszewska, Ebi, Dr. Peter Jarowski, and Kasper Lincke. A lot of people from other groups have also contributed to many fun moments in Zürich. Thanks foremost to Dr. Katja Chiesa, Dr. Martina Adams, Prof. Dr. Ryan Gilmour, and Dr. Karolin Geyer. I would especially like to thank Team Grützmacher, i.e. Matthias, Amos Rosenthal, and Dr. Mónica Trincado Rodríguez, for all the lunches, evenings, excursions all around Zürich, and, most of all, their friendship. I would like to thank Petra for her never-ending support, for the friendship, and for always being there for me. Lorenzo, muchas gracias por todo. Kiitos Äiti, Isä ja Iina tuesta ja kannustuksesta koko väitöskirjan ajan. Ja aina muutenkin. Olette tärkeimmät. Publications Laura M. Salonen, Mareike C. Holland, Philip S. J. Kaib, Wolfgang Haap, Jörg Benz, Jean-Luc Mary, Olivier Kuster, W. Bernd Schweizer, David W. Banner, and François Diederich, “Molecular Recognition at the Active Site of Factor Xa: Cation– Interactions, Stacking on Planar Peptide Surfaces, and Replacement of Structural Water”, in preparation. Laura M. Salonen, Manuel Ellermann, François Diederich, “Aromatic Rings in Chemical and Biological Recognition: Energetics and Structures”, Angew. Chem. Int. Ed. 2011, 50, 4808–4842. Laura M. Salonen, Christoph Bucher, David W. Banner, Wolfgang Haap, Jean-Luc Mary, Jörg Benz, Olivier Kuster, Paul Seiler, W. Bernd Schweizer, François Diederich, “Cation– Interactions at the Active Site of Factor Xa: Dramatic Enhancement upon Stepwise N-Alkylation of Ammonium Ions”, Angew. Chem. Int. Ed. 2009, 48, 811–814. Oral and Poster Presentations "Cation– Interactions in the S4 Pocket of Factor Xa", Laura M. Salonen, David W. Banner, François Diederich, SCS Fall Meeting 2009, Lausanne, Switzerland, 04.09.2009 (Oral Communication). “Cation– Interactions in the S4 Pocket of Factor Xa: Dramatic Enhancement upon Stepwise N-Alkylation of Ammonium Ions”, Laura M. Salonen, François Diederich, ASMC2009 Kiev, 3rd International Symposium on Advances in Synthetic and Medicinal Chemistry, Kiev, Ukraine, 23.–27.08.2009 (Oral Communication). “Cation– Interactions at the Active Site of Factor Xa”, Laura M. Salonen, David W. Banner, François Diederich, 2nd Symposium of the SSCI, ETH Hönggerberg, Zurich, Switzerland, 19.11.2009 (Poster Presentation). “Cation– Interactions at the Active Site of Factor Xa: Dramatic Enhancement upon Stepwise N-Alkylation of Ammonium Ions”, Laura M. Salonen, Christoph Bucher, David W. Banner, François Diederich, 1st Symposium of the SSCI, ETH Hönggerberg, Zurich, Switzerland, 28.11.2008 (Poster Presentation). “The Cation– Interaction in the S4 Pocket of Factor Xa”, Laura M. Salonen, Kaspar Schärer, David W. Banner, François Diederich, SCS Fall Meeting 2008, Zurich, Switzerland, 11.09.2008 (Poster Presentation). “The Quantification of Cation– Interactions in the S4 Pocket of Factor Xa”, Laura M. Salonen, Christoph Bucher, David W. Banner, François Diederich, EFMC-ISMC 2008 20th International Symposium of Medicinal Chemistry, Vienna, Austria, 31.08.– 04.09.2008 (Poster Presentation). Table of Contents Abbreviations...................................................................................................................I Summary....................................................................................................................... IV Zusammenfassung........................................................................................................VII 1. Introduction.................................................................................................................1 1.1. Molecular Recognition with Biological Systems................................................... 1 1.2. Cation– Interactions in Chemical and Biological Recognition............................. 2 1.3. The Human Blood Coagulation Cascade: Factor Xa and Thrombin....................... 8 1.4. Current Anticoagulant Therapy............................................................................13 1.5. Factor Xa and the Cation– Interaction................................................................15 1.6. Project Goals .......................................................................................................19 2. Enhancing Binding Affinity by S1 Needle Replacement.............................................21 2.1. Inhibitor Design: Exchanging
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