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Structural Bioinformatics: Modelling of Transport Processes

The Research Group Pharmaceutical Bioinformatics develops and applies theoretical methods for biochemical, biophysical, and pharmaceutical research. The group is highly connected to the participating principal investigators of the Research Training Group RTG 2202 and will provide these methods to support the doctoral students in their individual research projects. The fields of application include the modeling of biomolecules and molecular interactions, software development, analysis of high throughput data, or virtual screening.

Planned projects within the RTG 2202: 

Modelling of transmembrane transport of small molecules 

The P-glycoprotein (P-gp) is capable of effluxing a broad range of cytosolic and membrane penetrating xenobiotic substrates, thus leading to multidrug resistance and posing a threat for the therapeutic treatment of several diseases, including cancer and central nervous disorders. Herein, a virtual screening campaign followed by experimental validation in Caco-2, MDKCII, and MDKCII mdr1 transfected cell lines has been conducted for the identification of novel phospholipids with P-gp transportation inhibitory activity. C8:0 Phosphatidylinositol-sodium salt (PI) was found to significantly inhibit transmembrane P-gp transportation in vitro in a reproducible-, cell line-, and substrate-independent manner [1]. Further tests are needed to determine whether this and other phosphatidylinositols could be co-administered with oral drugs to successfully increase their bioavailability.

Comparisons of binding sites of GPCRs

The class of GPCR-proteins contains several famous drug targets. The trans-membrane receptors sense molecules outside the cell and activate inside signal transduction pathways and cellular responses. Binding site similarities between the homologue proteins have an important effect on drug responses because single drugs may elicit an activation or inhibition of several GPCRs in parallel (Fig.1) [2]. Within this research project binding sites of GPCRs are compared and classified to predict which drugs interact with which GPCRs.

Pathway modelling 

Streptomycetes are soil-living bacteria which produce a variety of important drugs [3]. The quantities produced are usually very low. The increasing resistance development urges the necessity to find alternatives to known active antibiotics and make them accessible in sufficient quantities. From a sequenced genome a complete metabolic model of the bacteria was built up. The model can be used to calculate the uptake through the membrane and the flow of metabolites within the metabolic network. Based on the results hypotheses can be generated how the bacteria has to be manipulated by genetic engineering to obtain an optimal production of biotechnologically important metabolites.



Figure 1: (a) Crystal structure of the beta-2-adrenergic receptor (ADRB2) with its inverse agonist carazolol (PDB-ID: 2rhi). (b) Average distance tree of 13 G protein-coupled receptors (GPCRs) represented by entry names of the UniProtdatabase . (c) ClustalW multiple sequence alignment of a part of the receptors ligand/drug binding sites [2].



[1] X. Lucas, S. Simon, R. Schubert, S. Günther. Discovery of the inhibitory effect of a phosphatidylinositol derivative on P-glycoprotein by virtual screening followed by in vitro cellular studies. PLoS One. 2013 Apr 9;8(4):e60679.

[2] R. Adams, C.L. Worth, S. Günther, M. Dunkel, R. Lehmann, R. Preissner. Binding sites in membrane proteins--diversity, druggability and prospects. Eur J Cell Biol. 2012 Apr;91(4):326-39.

[3] D. Klementz, K. Döring, X. Lucas, K.K. Telukunta, A. Erxleben, D. Deubel, A. Erber, I. Santillana, O.S. Thomas, A. Bechthold, S. Günther. StreptomeDB 2.0-an extended resource of natural products produced by streptomycetes. Nucleic Acids Res. 2016 Jan 4;44(D1):D509-14.




Prof. Dr. Stefan Günther

Pharmaceutical Bioinformatics
Hermann-Herder-Str. 9
79104 Freiburg

Phone: +49 (761) 203 4871 
Fax: +49 (761) 203 97769