Urszula Uciechowska
Chemist (MSc) Urszula Uciechowska
Tel. ++49 345 55 25 045
e-mail: urszula.uciechowska(at)pharmazie.uni-halle.de
Computer-based Development of Inhibitors for NAD+ dependent Histonedeacetlyases (Sirtuins)
Histone deacetylases from the Sir2 family have been implicated in transcription silencing and suppression of recombination. The Sir2 complex represses transcription at telomeres, mating-type loci, and ribosomal DNA. The Sir2 gene is highly conserved in organisms ranging from archaea to humans. Interestingly, Sir2 is active as an NAD+-dependent deacetylase (in contrast to the HDAC histone deacetylases, which are Zinc-dependent enzymes), which is broadly conserved from bacteria to higher eukaryotes.
To further analyze the function of human Sir2 enzymes, for which several subtypes have been detected so far, potent and subtype-selective inhibitors are needed. For the human Sirtuin subtype II the crystal structure has been recently described which will now be used for structure-based design of inhibitors. The docking of the lead compound splitomycin resulted in a hypothesis for the binding mechanism of this molecule. On the basis of a variety of different theoretical approaches we have designed modified splitomycin derivatives which have been synthesized and tested by our collaboration partner Prof. Manfred Jung in Freiburg. The novel compounds are active in the sub-micromolar range on Sirtuin subtype II with a moderate selectivity towards subtype I and III. In the ongoing projects we are interested in further optimizing the inhibitors (activity and selectivity) using theoretical and analytical methods. To investigate the selectivity profile of the compounds we have generated in addition a homology model for the human subtype I and III. The aim is to derive potent ligands to analyze the therapeutic potential of this new drug family in detail.
Publications
K. Huber, J. Schemies, U. Uciechowska, J. M. Wagner, T. Rumpf, F. Lewrick, R. Süss, W. Sippl, M. Jung and F. Bracher
Novel 3‑Arylidene-indolin-2‑ones as inhibitors of NAD+-dependent histone deacetylases (sirtuins)
J. Med. Chem. 2010, 53,1383-1386
J. Schemies, U. Uciechowska, W. Sippl and M. Jung
NAD+ dependent histone deacetylases (sirtuins) as novel therapeutic target.
Med Res Rev, 2009, in press.
U. Uciechowska, J. Schemies, R. Neugebauer, E. Huda, M. Schmitt, R. Meier, E. Verdin, M. Jung, W. Sippl
Thiobarbiturates as Sirtuin Inhibitors: Virtual Screening, Free Energy Calculations and Biological Testing.
Chem.Med.Chem., 2008, 3(12), 1965-1976
R. C. Neugebauer, U. Uciechowska, R. Meier, H. Hruby, V. Valkov, E. Verdin, W. Sippl, and M. Jung
Structure activity studies on splitomicin derivatives as sirtuin inhibitors and computational prediction of binding mode.
J. Med. Chem. 51, 1203- 1213, 2008
Poster Abstracts
J. M. Wagner, J. Schemies, K. Huber, U. Uciechowska, T. Rumpf, F. Bracher, W. Sippl, M. Jung
New inhibitors of NAD+ dependent histone deacetylases (sirtuins) with cellular activity
ICC on Sirtuins 2009,
Barcelona, 22.-23.10.2009
M. Jung, M. Schmitt, J. Schemies, R. Rumpf, J. Wagner, U. Uciechowska,
W. Sippl
Thiobarbiturate inhibitors of NAD+ dependent histone deacetylases (sirtuins)
Frontiers in Medicinal Chemistry
Barcelona, 04.-06.10.2009
U. Uciechowska, J. Schemies, M.L. Schmitt, M. Jung, W. Sippl
Prediction of ligand binding free energies of novel thiobarbiturates to the human NAD+ dependent histone deacetylase Sirt2
Jahrestagung der Deutschen Pharmazeutischen Gesellschaft
Jena, 29.09. - 01.10. 2009.
U. Uciechowska, J. Schemies, M. Jung, W. Sippl
Prediction of ligand binding free energies of novel thiobarbiturates to the human NAD+ dependent histone deacetylase Sirt2
Molecular Modelling Conference
Erlangen, 06.-08.09.2009.
J. Schemies, U. Uciechowska, M.L. Schmitt, W. Sippl, M. Jung.
Novel inhibitors of NAD+ dependent histone deacetylases (sirtuins) with a thiourea structure.
3rd European Conference on Chemistry for Life Sciences.
Frankfurt, 02.-05. 09.2009
U. Uciechowska, J. Schemies, M. L. Schmitt, E.-M. Huda, M. Jung, W. Sippl Prediction of binding free energies of NAD+ dependent histone deacetylase inhibitors
5th German-Polish Symposium on Pharmaceutical Sciences
Posen, 15.-05.-17.05.2009
U. Uciechowska, J. Schemies, R. Neugebauer, M. Jung, W. Sippl
Binding free energy calculations of sirtuin inhibitors
15th Int. Symposium Medicinal Chemistry
Wien, 31.08.-05.09.2008
U. Uciechowska, J. Schemies, R. Neugebauer, M. Jung, W. Sippl
Identification of novel sirtuin inhibitors by virtual screening
and binding free energy calculations.
3. Mildred Scheel Cancer Conference
Königswinter 18. - 20. 06. 2008
J. Schemies, K. Huber, U. Uciechowska, F. Bracher, W. Sippl, M. Jung
Arylidene-indolones as new potent inhibitors of NAD+
dependent histone deacetylases (sirtuins).
3. Mildred Scheel Cancer Conference
Königswinter 18. - 20. 06. 2008
J. Schemies, K. Huber, U. Uciechowska, F. Bracher, W. Sippl, M. Jung
New inhibitors of NAD+ dependent histone deacetylases (sirtuins).
Screening Europe 19. - 20. 02. 2008; Stockholm, Schweden
M. Jung, J. Schemies, K. Huber, U. Uciechowska, F. Bracher and W. Sippl
New inhibitors of NAD+ dependent histone deacetylases (sirtuins)
European School of Oncology (ESO) - Centro Nacional de Investigaciones Oncologicas (CNIO) -
Epigenetics and new therapies in cancer
29.-30-11.2007 Madrid, Spanien
U. Uciechowska, R. Neugebauer, M. Jung, W. Sippl
Splitomicin Derivatives as Sirt2 Inhibitors – Computational Prediction of the Binding Mode
Jahrestagung der Deutschen Pharmazeutischen Gesellschaft
Erlangen,10.-13.10.2007.
U. Uciechowska, R. Neugebauer, M. Jung, W. Sippl
Docking and Molecular Dynamics Studies on Novel Sirtuin Sirt2 Inhibitors
21. Darmstädter Modelling Workshop
Erlangen, 16.-17.05.2007