Dominik Schnalzer

Supervisor: Marko Mihovilovic, Technical University of Vienna

Co-Supervisor: Margot Ernst, Medical University of Vienna


Start of project: 01.08.2019

Title of the project: Developing Labelled Ligands as Tool Compounds for Mechanistic Studies on the GABAA-Receptor and Other Ion Channels


Research topic of the student: 

During the previous funding periods of the MolTag program, several novel chemo-types for GABAA-receptor modulators were identified and characterized, enabling access to a number of tool compounds. This platform of structures (in combination with data from the literature9 provides a unique opportunity to include mechanistic studies involving radioisotopes such as tritium (3H) or carbon-14 (14C) to obtain a more comprehensive picture of binding properties. Furthermore, photoaffinity labeling (PAL) for a more in-depth investigation of the binding site of these compounds will be used. PAL probes are multicomponent tool compounds useful for identifying the location of the binding site by covalently capturing transient molecular interactions. Essential to this mechanism are drug molecules bearing photo-cross linkers such as trifluoromethyl phenyl diazirines which generate highly reactive carbene species upon irridiation with UV-light. The reactive intermediates then rapidly form covalent cross-links to the protein target.  

The overall goal of this project is the development of strategies and methods to incorporate labeling  moieties (i.e. radioisotopes and/or photo-cross-linking units) into the compounds of interest while maintaining target affinity to obtain detailed insight into interactions of  ligands with their protein targets. This information should facilitate making predictions with computaitonal models (e.g. prediction of binding  modes) and ultimately help to design novel ligands for ion channels.  


Internship abroad: "Electrophysiological Studies on the GABAA-receptor with Potential alpha+/beta1- ECD Pocket Selective Pyrazoloquinolinones"; 01.03.2022 - 31.05.2022

Host lab: Department of Neurology, Dell Medical School, The University of Texas at Austin, USA

Lab rotation: "Electrophysiological Characterisation of R6-Substituted Pyrazoloquinolinones as GABAA-Receptor Modulators in Xenopus laevis Oocytes"; 31.01.-21.02.2022

Lab host: Margot Ernst, Medical University of Vienna