Philipp Kohler

 

PhD Student

Location:

HCI G-327

Phone:

+41-44-632 2953

e-mail:

External Page

Philipp Kohler

Education

2001-2005

Study of chemistry at ETH Zurich

2005:

Diploma thesis with Prof. F. Diederich at ETH Zurich

2006:

Internship at F. Hoffmann-La Roche, Basel

since 2006:

PhD with Prof. F. Diederich at ETH Zurich


Crystal structure of Y106F mutated TGT complexed with preQ1. R. Brenk et al., ChemBioChem 2003, 4, 1066-1077. PDB code 1OZQ.

Rational design and synthesis of tRNA-guanine transglycosylase (TGT) inhibitors

Bacterial dysentery, or shigellosis, is a disease affecting more than 160 million people each year. Symptoms include mucous or bloody diarrhoea, vomiting, abdominal pain and fever. The causing agent is the Gram-negative bacterium Shigella, which is closely related to E. coli. It has been shown that the virulence of Shigella is closely linked to the tRNA modifying enzyme tRNA-guanine transglycosylase (TGT) that exchanges guanine for the hypermodified base preQ1. TGT is therefore a viable target for the development of new drugs against shigellosis.
By rational structure-based ligand design based on crystal structures of the enzyme with bound substrate or inhibitors, good progress has already been made in cooperation with the group of G. Klebe in Marburg. The lin-benzoguanine scaffold has proved to be a good starting point for further optimization. The current goal is to address the ribose 33 binding site, where a hydrophobic cleft is located, with 2-substituted lin-benzoguanines. Furthermore, we want to fill the hydrophobic pocket formed by Val282, Val45 and Leu68 with a small (hetero-)aromatic ring. The program MOLOC will be used for molecular modeling to support the design process.

Publications

T. Ritschel, P. C. Kohler, G. Neudert, A. Heine, F. Diederich, G. Klebe, ChemMedChem 2009, 4, 2012-2023. How to Replace the Residual Solvation Shell of Polar Active-site Residues to Achieve Nanomolar Inhibition of tRNA-Guanine Transglycosylase

P. C. Kohler, T. Ritschel, W. B. Schweizer, G. Klebe, F. Diederich, Chem. Eur. J. 2009, 15, 10809-10817. High-Affinity Inhibitors of tRNA-Guanine Transglycosylase Replacing the Function of a Structural Water Cluster.

P. Hebeisen, B. Kuhn, P. Kohler, M. Gubler, W. Huber, E. Kitas, B. Schott, J. Benz, C. Joseph, A. Ruf, Bioorg. Med. Chem. Lett. 2008, 18, 4708-4712. Allosteric FBPase Inhibitors Gain 105 Times in Potency When Simultaneously Binding Two Neighboring AMP Sites.

W. Haap, P. Hebeisen, E. A. Kitas, P. C. Kohler, H. Kuehne, A. Ruf, PCT Int. Appl. 2008, WO 2008037628. Preparation of (hetero)aryl disulfonylureas as antidiabetics.

B. Stump, P. C. Kohler, W. B. Schweizer, F. Diederich, Heterocycles 2007, 72, 293-326. Synthesis of 2,4,5-Trisubstituted Thiazoles with a 5-(N,N-Dimethylaminomethyl) Substituent.

Last update: Dec. 2009