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Research Report 2003 I 2004

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Research Report 2003 I 2004 FORSCHUNGSINSTITUT FÜR MOLEKULARE PHARMAKOLOGIE IM FORSCHUNGSVERBUND BERLIN E. V. RESEARCH REPORT 2003 I 2004 IM FORSCHUNGSVERBUNDBERLINE FÜR MOLEKULAREPHARMAKOLOGIE FORSCHUNGSINSTITUT .V. 2003 I2004 RESEARCH REPORT FORSCHUNGSINSTITUT FÜR MOLEKULARE PHARMAKOLOGIE Campus Berlin-Buch Robert-Rössle-Str. 10 D-13125 Berlin fon: +49-(0)30-94793-100 fax: +49-(0)30-94793-109 e-mail: [email protected] Outstation: Department of Molecular Genetics FEM Steglitz Krahmerstr. 6-10 D-12207 Berlin fon: +49-(0)30-8437-1910 fax: +49-(0)30-8437-1922 The Forschungsinstitut für Molekulare Pharmakologie (FMP) evolved out of the Institut für Wirkstoffforschung (IWF) of the Academy of Sciences of the GDR. Together with seven other research institutions, the institute is administratively organized within the Forschungsverbund Berlin e.V. The FMP is a member of the Leibniz Association. Das Forschungsinstitut für Molekulare Pharmakologie ist aus dem Institut für Wirkstoffforschung (IWF) der Akademie der Wissenschaften der DDR hervor- gegangen. Es ist mit sieben weiteren Forschungsinstituten im Forschungs- verbund Berlin e.V. zusammengeschlossen. Das FMP ist ein Mitglied der Leibniz-Gemeinschaft. RESEARCH REPORT 2003 / 2004 FORSCHUNGSINSTITUT Editorial Board: FÜR MOLEKULARE PHARMAKOLOGIE Walter Rosenthal, Michael Bienert, Ivan Horak, Hartmut Oschkinat IM FORSCHUNGSVERBUND BERLIN E.V. Compilation & Editing: Björn Maul Cover Design and Layout: Hoch3 GmbH, Berlin Photos: Bernhard Schurian, Thomas Oberländer, Björn Maul, Dana Hausbeck FMP Print: Druckhaus Berlin-Mitte This Research Report is also available at www.fmp-berlin.de Cover: The G-Protein coupled receptor GPR 109: binding site with ligand (nicotinic acid) SCIENTIFIC ADVISORY BOARD WISSENSCHAFTLICHER BEIRAT Professor Dr. Rudolf Balling GBF - Gesellschaft für Biotechnologische Forschung mbH Mascheroder Weg 1 38124 Braunschweig Professor Dr. Annette G. Beck-Sickinger Institut für Biochemie der Universität Leipzig Brüderstr. 34 04103 Leipzig Professor Dr. Matthias Bräutigam Schering AG Müllerstr. 170-178 13342 Berlin Professor Dr. Christian Griesinger Max-Planck-Institut für Biophysikalische Chemie Am Faßberg 11 37077 Göttingen Professor Dr. Reinhard Jahn (Vorsitz) Max-Planck-Institut für Biophysikalische Chemie Am Faßberg 11 37077 Göttingen Professor Dr. Hans-Georg Joost Deutsches Institut für Ernährungsforschung Arthur-Scheunert-Allee 114 14558 Potsdam-Rehbrücke Professor Dr. Frauke Melchior Universitätsklinikum der Georg-August-Universität Göttingen Zentrum für Biochemie und Molekulare Zellbiologie Humboldt-Allee 23 37073 Göttingen Professor Dr. Herbert Waldmann Max-Planck-Institut für Molekulare Physiologie The Scientific Advisory Board of the FMP formally consti- Otto-Hahn Str. 11 tuted itself at its meeting on November 6, 1992. At the 44202 Dortmund board meeting on November 16, 2000 Professor Reinhard Jahn was elected chairman. Der Wissenschaftliche Beirat des FMP konstituierte sich anläßlich seiner Sitzung am 6. November 1992. Auf der Sit- zung am 16. November 2000 wurde Professor Dr. Reinhard Jahn zum Vorsitzenden gewählt. The FMP undertakes research in the field of molecular stry, was established alongside peptide chemistry. At the pharmacology. In accordance with this objective, the FMP same time a Screening Unit was built up, making substan- strives to make contributions of fundamental significance. ce libraries and screening technology available. Jens In this context, it is engaged in elucidating the structure, Peter von Kries could be recruited to direct it. The FMP is functions and interactions of proteins and in developing thus the first academic institution in Germany which, using new concepts relating to their pharmacological impact. high throughput methods, can identify small molecules Thus, the research activity of the FMP is at the forefront of that bind to specific proteins and develop a biological drug development. The FMP pursues an interdisciplinary effect (pages 92-95). These small molecules represent research approach, which has brought together cellular important tools for research. At the same time they can signal transduction/molecular genetics, structural biolo- also be regarded as prototypes of novel pharmaceuticals. gy and chemical biology. Characteristic for the scientific FMP scientists are centrally involved in building up a new work at the FMP is the close interrelationship of chemi- national network (ChemBioNet; www.chembionet.de), stry and biology. through which academic groups can obtain access to sub- stance libraries and screening technology. MILESTONES 2003/2004 With the establishment of the research group Solid State NMR and the appointment of group leader Bernd Reif as The years 2003/4 were characterized by the expansion of Professor for Drug Design (joint appointment of the FMP the chemistry department. With the appointment of Jörg and the Charité – University Medicine Berlin), the staff of Rademann as Professor for Medicinal Chemistry (joint the NMR Center of the FMP was greatly expanded. An out- appointment by the FMP and the Free University Berlin), a standing event was also the first-time operation of the 900 new important area of competence, combinatorial chemi- MHz spectrometer, which represents the current state-of- d r o w e r o F FOREWORD 3 Das FMP betreibt Forschung auf dem Gebiet der Moleku- Screening Unit aufgebaut, die über Substanzbibliotheken laren Pharmakologie. Dabei ist es bestrebt, Beiträge von und Screening-Technologie verfügt. Als Leiter konnte grundsätzlicher Bedeutung zu erbringen. In diesem Rah- Jens Peter von Kries gewonnen werden. Damit ist das men versucht es, die Struktur, Funktionen und Interaktio- FMP die erste akademische Einrichtung in Deutschland, nen von Eiweißen (Proteinen) aufzuklären und neue Kon- die kleine Moleküle, die an bestimmte Proteine binden und zepte zu ihrer pharmakologischen Beeinflussung zu eine biologische Wirkung entfalten, im Hochdurchsatzver- entwickeln. Damit ist die Forschungstätigkeit des FMP im fahren identifizieren kann. Diese kleinen Moleküle stellen Vorfeld der Entwicklung von Arzneimitteln angesiedelt. wichtige Werkzeuge für die Forschung dar. Zugleich sind Das FMP verfolgt einen interdisziplinären Forschungsan- sie aber auch als Prototypen neuartiger Pharmaka zu satz, der zur Zusammenführung von Zellulärer Signaltrans- betrachten. Wissenschaftler des FMP sind auch in zentra- duktion/Molekularer Genetik, Strukturbiologie und Chemi- ler Weise am Aufbau eines nationalen Netzwerks (Chem- scher Biologie geführt hat. Kennzeichnend für die BioNet; www.chembionet.de) beteiligt, durch das akade- wissenschaftliche Arbeit am FMP ist die enge Verknüp- mische Gruppen Zugang zu Substanzbibliotheken und fung von Chemie und Biologie. Screening-Technologie erhalten sollen. Mit der Einrichtung der Arbeitsgruppe Festkörper-NMR MEILENSTEINE 2003/2004 und der Berufung eines Leiters, Bernd Reif, auf eine Pro- fessur für Drug Design (gemeinsame Berufung von FMP Die Jahre 2003/2004 waren durch den Ausbau der Chemie und Charité – Universitätsmedizin Berlin) wurde das NMR- geprägt. Durch die Berufung von Jörg Rademann auf eine Zentrum des FMP personell stark erweitert. Ein heraus- Professur für Medizinische Chemie (gemeinsame Beru- ragendes Ereignis war auch die Inbetriebnahme eines fung von FMP und Freier Universität Berlin) wurde neben 900 MHz-Spektrometers, das den aktuellen Stand der Ent- der Peptidchemie ein neuer Schwerpunkt „Kombina- wicklung repräsentiert. Weltweit sind erst wenige Geräte torische Chemie“ geschaffen. Gleichzeitig wurde eine dieses Typs verfügbar. Die erforderlichen Mittel (insge- the-art development. Worldwide only a few devices of this type are in existence. The necessary funding (totaling 4.9 million ?) was provided by the BMBF (Federal Ministry of Education and Research) in the framework of a project grant and the Berlin Senate Department for Science, Research and Culture (EFRE funds). Thus an outstandingly well-equipped and well-staffed center for structural bio- logy oriented NMR spectroscopy has been created that has an international reputation. In June 2003 at a ceremony which included the governing mayor of Berlin, the cornerstone was laid for the new Medicinal Genomics Building. It is a joint initiative of the FMP and the Max Delbrück Center for Molecular Medicine (MDC). The striking building, designed by the Staab archi- tectural bureau, provides lab and office space for a staff of 120. The move into the new building will take place in autumn 2005. Of the 230 employees on the staff of the FMP, about 40 will work in the new building. FOREWORD samt 4,9 Mio ?) wurden vom BMBF im Rahmen der Pro- PERSPEKTIVEN jektförderung und der Berliner Senatsverwaltung für Wis- senschaft, Forschung und Kultur (EFRE-Mittel) zur Verfü- Arzneimittel entfalten ihre Wirkung durch Interaktion ihrer gung gestellt. Damit ist ein gerätemäßig und personell Inhaltsstoffe (Wirkstoffe) mit körpereigenen Strukturen. hervorragend ausgestattetes, international ausstrahlen- Bei diesen Andockstellen im Organismus (Zielstrukturen, des Zentrum für die strukturbiologisch orientierte NMR- „targets“) handelt es sich fast ausnahmslos um Proteine Spektroskopie etabliert. (> 99%). Bisher ist erst ein sehr kleiner Teil der Eiweiße des menschlichen Körpers als Zielstruktur für einen Wirkstoff Im Juni 2003 wurde gemeinsam mit dem Max-Delbrück- erschlossen (ca. 500). Sicher kommen nicht alle 100.000 Centrum für Molekulare Medizin (MDC) im Beisein des Eiweiße des Organismus als „targets“ für Wirkstoffe in Regierenden Bürgermeisters
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