Jure Fabjan, BSc
Department(s): Department of Pathobiology of the Nervous System (Center for Brain Research)
Position: PHD Student
Location: Spitalgasse 4
Many GABAA receptor targeting chemotypes can interact with distinct binding sites on a given receptor pentamer. Only a small share of allosteric sites has been studied (e.g. the benzodiazepine binding site), leaving a gap in the understanding of the pharmacotoxicology mediated by other allosteric sites. We focus on resolving the binding profiles of compound classes with complex ligand-receptor interactions. Furthermore, acute and chronic effects of GABAA receptor targeting drugs can be very different due to extensive neuroplasticity. Thus, we explore the effects of acute versus chronic drug exposure in animals on the single cell level.
In case of GABAA receptors, correlating functional profiles with binding sites usage is often hampered by scarce and heterogeneous experimental data. Furthermore, for a lot of compound classes the bound experimental structures are absent. We make use of two-electrode voltage clamp electrophysiology of expressing Xenopus laevis oocytes to characterize the functional effect of the compounds on various GABAA receptors. In this line of work, binding site usage is probed with mutational analysis. For the guided ligand development not only extensive experimental data, but also solid structural hypotheses of binding are needed. To explore the structure-activity landscape, we use computational docking and pharmacophore matching methods to predict bound states for individual compounds. To explore effects of acute and repeated exposure in rats we make use of bulk-tissue and single-cell RNA sequencing.
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