Eliane Schweizer

 

PhD Student

Location:

HCI G-312

Phone:

+41-1-633 4169

e-mail:

Eliane Schweizer

Education

1997-2002:

Study of biochemistry at ETH Zurich

2002:

Diploma thesis with Prof. F. Diederich at ETH Zurich

since 2002:

PhD in medicinal chemistry with Prof. F. Diederich at ETH ZŸrich

Project

Thrombin is a serine protease involved in the blood-clotting cascade. A dysfunction of this protein causes vascular diseases such as thrombotic disorders and therefore the inhibition of this coagulation factor is a main target in the pharmaceutical research. In our group a novel series of tricyclic inhibitors has been synthesised and their inhibitory potency could be enhanced by introduction of a fluorine substituent in position 4 of the benzylmaleimide moiety (Figure 1), leading to the discovery of an underestimated type of multipolar interaction between the halogen and the backbone carbonyl group of Asn 98 in the distal pocket. At this stage, the aim of the project is to investigate the presence of other multipolar interactions in the active site of the enzyme, by replacing the fluorine with other residues such as a hydroxy or methoxy group or a halogen, and by systematically exchanging every hydrogen of the pyrrolidine ring reaching into the oxyanion hole with fluorine, OH or OMe. Further, the impact on the inhibitory constant by variation of the residue pointing towards the proximal pocket will be analysed.


Figure 1         Our so far most potent thrombin inhibitor bound into the active site of the enzyme.