Project I - The molecular basis of drug-transporter interaction in the SLC6 family

In the previous two funding periods as well as in light of our contribution to the SFB35 (sfb35.at) and the RESOLUTE project (www.re-solute.eu) we are developing ligand- and structure-based models for ligands of the neurotransmitter transporters SERT, DAT, and NET as well as for the GABA transporters. In this project we will focus on the molecular basis of ligand-transporter selectivity (both for SERT/DAT/NET and for GAT1-4), as well as expand our studies to the taurine and carnitine transporter. The project combines data science approaches (creating and curating data sets from public data repositories via semi-automatic tools) with ligand and structure based in silico approaches (creating protein homology models, performing QSAR analyses, pursuing experimental data driven docking) and virtual screening. Furthermore, proteochemometric methods as well as the PaMLAC approach (Paired Mutant Ligand Analogue Complementation Assay) as described by Celik et al. for SERT (JACS 2008) will be implemented. Binding hypotheses retrieved will be experimentally validated by our collaboration partners in the consortium and will form the basis for virtual screening campaigns. Most promising compounds retrieved will be subject to structural modifications (Mihovilovic and Maulide lab) and further experimental characterisation (Sitte lab, external collaboration Wellendorph). Furthermore, the concept might be generalised for other transporter and ion channels.

Project II - Probing bile acid recognition by ABC- and SLC-transporters and nuclear receptors

Bile acids are potent signaling molecules that regulate glucose, lipid and energy homeostasis predominantly via the bile acid receptors, farnesoid X receptor (FXR) and transmembrane G protein-coupled receptor 5 (TGR5). The sodium taurocholate cotransporting polypeptide (NTCP), the apical sodium dependent bile acid transporter (ASBT), as well as the bile salt export pump (BSEP) ensure an effective circulation of (conjugated) bile acids. While NTCP and ASBT belong to the family of SLC transporter, BSEP is an ABC-transporter. In this project we plan to dissect the molecular recognition principle for bile acids and analogs which are common to such diverse proteins as ABC-transporter, SLC-transporter, nuclear receptors and GPCRs. Based on work on BSEP performed in funding period 2, protein homology models (Ernst and Weinzinger labs) will be generated for the remaining 4 targets and bile acids and analogs will be docked into the models following our data guided docking approach [Sarker 2010, Klepsch 2011, Richter 2012, Jain 2017]. Based on this, structure-based pharmacophore models for profiling compounds against all five proteins will be developed and used for virtual screening. [Jurik et al. 2015] This will allow identifying compounds which either selectively target one of these proteins or show multitarget inhibitor profiles.