Simone Hörtner


PhD Student


HCI G-306


+41-44-632 29 12


Simone Hörtner



Basic Studies (1.-4. Semester, Dept. of Biology, Branch of Study: Chemistry-Biology, ETH Zurich


Special Studies (5. and 6. Semester, Dept. of Chemistry, Branch of Study: Chemistry-Biology / Chemistry, University of Cambridge, UK


Special Studies (7. and 8. Semester, Dept. of Biology, Branch of Study: Chemistry-Biology / Chemistry and Diploma Thesis with Prof. F. Diederich at ETH Zurich


Diploma of Natural Sciences


PhD Thesis with Prof. F. Diederich

Industrial Experience


Literature Research and Compilation of a Database for Folic acid derivates, focussing on 5-Methyltetrahydrofolic Acid and Cellculture Assays based on the gathered Information (6 months), 1999 Eprova AG, Schaffhausen


Project Work in the field of organic synthesis: Preparation of an Inhibitor Library (4 months), F. Hoffmann-La Roche, Division Pharma, Lead Generation, Basel


Short term employment in the R&D department of Folic acid derivates: Stereospecific Synthesis of (6S)-Tetrahydrobiopterin (7 months), Merck-Eprova AG, Schaffhausen

Structure-Based Design and Synthesis of Inhibitors of Eubacterial tRNA-Guanine Transglycosylase (TGT)

TGT with substrate preQ1 (2.2 Å).  C. Romier et al. EMBO J. 1996, 15, 2850

tRNA-guanine transglycosylase (TGT) plays a key role in the post-transcriptional modification of tRNA.  This enzyme is common to nearly all organisms, including humans, whereas its substrate specificity arises from its phylogenetic origin.  In prokaryotes and in higher organisms the endproduct of the TGT dependent biosynthesis is the highly modified nucleobase queuine, whose physiological function is still unclear.  TGT has been linked with the pathogenicity of the shigellae, the causative agents of bacillary dysentery.  Extensive crystallographic and biochemical characterizations makes TGT an ideal target for structure based drug design and might facilitate the development of antibiotics against dysentery.
Based on the X-ray crystal structure of TGT in complex with its substrate or known ligands and using molecular modeling tools, new classes of inhibitors will be designed.
Preliminary work carried out in our Group (E. Meyer and co-workers) led to a detailed analysis of the active site of the target enzyme as well as strong inhibitors based on amino-quinazolinone and lin-benzoguanine as core structures.
As the 2-amino-quinazolinone scaffold displays excellent binding properties, it is further investigated.  In order to strengthen its binding to the active site, substituents (dimethylamine, benzyl-methyl-amine, 2-morpholin-4-yl-ethylamine) are positioned at C(7) as substitution at position (8) resulted in modest binding.  This might be due to distortion of water molecules in the active site, that solvate the polar, partially charged residues located at the edge of the lipophilic pocket.  Using an amine as linker between the core and the substituent allows for H-bonding of the water located in the active site thereby solvating the polar, partially charged residues, rather then displacing the water, according to MOLOC, the molecular modeling program used for this project.
A subsequent set of inhibitors will be based on lin-benzoguanine, but instead of substituting the 4-position, different moieties will be linked to C(2).  This change probes the available space in that region of the enzyme, as this is the tRNA binding site and additionally this is approach to reach the lipophilic pocket without disturbing the residual water molecules.  Firstly, small residues like methyl-, amino- and hydroxy-groups will be introduced.  These products are designed for being potential inhibitors as well as precursors for molecules carrying larger substituents.   A further target is the proximal-benzoguanine, which displays excellent binding properties towards the hydrophilic environment of the solvated catalytic acid/base (Asp102), according to molecular modeling studies.


D. A. Carcache, S. R. Hörtner, A. Bertogg, C. Binkert, D. Bur, H. P. Märki, A. Dorn, F. Diederich, ChemBioChem 2002, 31, 1137-1141. De novo Design, Synthesis, and In vitro Evaluation of a New Class of Nonpeptidic Inhibitors of the Malarial Enzyme Plasmepsin II.

D. A. Carcache, S. R. Hörtner, P. Seiler, F. Diederich, A. Dorn, H. P. Märki, C. Binkert, D. Bur, Helv. Chim. Acta 2003, 86, 2173-2191. Development of a New Class of Inhibitors for the Malarial Aspartic Protease Plasmepsin II Based on a Central 7-Azabicyclo[2.2.1.]heptane Scaffold.

D. A. Carcache, S. R. Hörtner, A. Bertogg, F. Diederich, A. Dorn, H. P. Märki, C. Binkert, D. Bur, Helv. Chim. Acta 2003, 86, 2192-2209. A New Class of Inhibitors of the Malarial Aspartic Protease Plasmepsin II Based on a Central 11-Azatricyclo[,7]undeca-2,4,6-triene Scaffold.