Thesis work —Mechanistic studies on the pathways leading to covalent binding of drug molecules to protein targets

Formation of reactive metabolites from drug molecules and the covalent binding of these reactive metabolites to proteins are proposed to be involved in adverse drug reactions and constitute a safety risk for drug candidates under development. Chemical trapping and other reactivity studies had led to the identification of different types of reactive metabolites with propensity to react with biological nucleophiles. Although there is a good understanding about the formation of electrophilic reactive metabolites, there is less know about the biological nucleophiles and the nature of the small molecule-protein adducts.

In this work, the exam worker will study in particular the reactivity of iminium ions, aldehydes and acyl glucuronides and their interactions with biological nucleophiles with the aid of biochemical and bioanalytical approaches utilizing radiolabelled drug molecules.The work will also involve the PK/PD modelling of covalent binding of drug molecule to proteins

Your role
The work will involve in vitro incubations with radiolabelled compounds, covalent binding studies and metabolite/adduct analysis using LC-MS and radioflow detection. The results of the covalent binding studies will be followed by PK/PD modelling.

Your experience
Experience in fundamental biochemical techniques particularly in vitro incubations as well as a bioanalytical background is desired with basic knowledge of LC-MS and preferably radiochemical detection.

Work at AstraZeneca
Undertaking an exam work at AstraZeneca provides the individual with the opportunity to work in an intellectually stimulating scientific environment, with access to high technology equipment. Through the guidance provided by expert scientists, the students will have the chance to improve their knowledge while gaining hands on experience. During the exam work period, the students will also have the opportunity to be exposed to the working environment at a leading pharmaceutical company.

More information
Please contact Emre Isin, [email protected] +46 31 7064227 or Richard Thompson, [email protected] +46 31 7062567 for more information.

Closing date: June 9th. We will only handle applications received via www.astrazeneca.se .