Details

Title of the project: Computational Studies of SLC Transporters with Special Focus on the GABA Transporter Subfamily

Finishing date: 14.04.2020

Research topic of the student: Imbalance in the levels of the inhibitory neurotransmitter GABA can cause serious CNS related diseases such as depression, anxiety, schizophrenia and epilepsy. A promising approach in the treatment of epilepsy is to increase levels of GABA in the synaptic cleft by inhibiting its reuptake into neuronal and glial cells. The reuptake of GABA is facilitated by four different GABA transporters (GATs). Furthermore, the taurine transporter (TauT) is considered to be an “honorary” GAT as it shares high sequence identity with the GATs and is also capable of transporting GABA. So far, the structural basis for GAT and TauT selectivity is not well understood due to a lack of highly selective tool compounds. In April 2016, the crystal structure of the homologous human serotonin transporter (hSERT) was resolved. This new crystal structure not only confirms structural knowledge derived from earlier published crystal structures of bacterial homologous, but also gives exciting new insights by confirming a previously postulated allosteric binding site in hSERT. With the help of these homologous crystal structures, this work will give further insights into the selectivity profile of GABA and taurine transporters by applying structure-based computational methods such as homology modeling, molecular docking, molecular dynamics simulations, and free energy caclulations. The findings of this thesis will contribute to the design of new highly selective and potent tool compounds. 

Publications: https://www.ncbi.nlm.nih.gov/pubmed/

Research stays abroad: (1) 02.04.2018 – 31.08.2018 Host: William L. Jorgensen, Department of Chemistry, Yale University, New Haven/CT, USA. Topic: “Free Energy Calculations of Janus Kinase 2 inhibitors” 

(2) 20.02.-27.03.2019, Host: Petrine Wellendorph, Dept. of Drug Design and Pharmacology, Univ. of Copenhagen, DK. Topic:  broadening the understanding of pharmacological data, dataset for QSAR studies and proteochemometric approaches

Lab Rotation (3+ weeks): Host: Margot Ernst , Dept. of Molecular Neurosciences, Medical University of Vienna. Subject: Homology Modeling, 2016

Place after Graduation: PostDoc Grant of the Lundbeck Foundation Denmark; University of Copenhagen, Dept. of Drug Design and Pharmacology

Related Links: https://pharminfo.univie.ac.at/people/stefanie-kickinger/

Humans of the University of Vienna, Blog post (07/2020): https://blog.univie.ac.at/en/researchers-from-all-over-the-world-were-able-to-join/