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The Department of Biomedicine

BBB seminar: Ruth Brenk

Using crystal structures for ligand design – Druggability predictions, riboswitches and kinases

Ruth Brenk
Department of Biomedicine, University of Bergen

Structure-based ligand design is an integral part of modern drug discovery. It makes use of the knowledge of the crystal structure of the target for the design of new ligands. In my group, we develop computational methods for structure-based design and apply such methods for the design of new ligands. In this seminar, I will present some ongoing research projects of my group, in particular I will report on our efforts to estimate if a target is druggable and on the design of riboswitch ligands and novel kinase inhibitors.

Judging if a protein is able to bind orally available molecules with high affinity, i.e. if a protein is druggable, is an important step in target assessment. We have derived a computational method to predict if a target is druggable. I will present this method along with our efforts to make this method applicable for large-scale target assessment.

Riboswitches are cis-acting gene regulatory elements that are mostly found in bacteria. They are located in the 5' untranslated region of mRNAs and consist of an aptamer domain that binds the ligand, and an expression platform that controls the expression of the downstream gene. The RNA can adopt one of several alternative conformations, the relative stability of which is determined by the binding of the ligand to the aptamer domain. Binding of the ligand directs folding of downstream elements in the expression platform that influence expression. The extent of the regulation of gene expression is controlled by the concentration of the small molecule ligand via the structure of the RNA. As such, they constitute novel targets for antibiotics. I will show how we demonstrated that RNA-ligand docking is as a suitable tool for hit discovery for riboswitches and our progress on hit discovery for the flavin mononucleotide (FMN) riboswitch, which is a possible target for antibiotics.

Protein kinases constitute an attractive family of enzyme targets with high relevance to cell and disease biology. Small molecule inhibitors are powerful tools to dissect and elucidate the function of kinases in chemical biology research and to serve as potential starting points for drug discovery. However, the discovery and development of novel inhibitors remains challenging. I will report on our structure-based de novo design approach that generates novel, hinge-binding fragments that are synthetically accessible and can be elaborated to small molecule libraries.


Chairperson: Aurora Martinez <aurora.martinez@uib.no>, Department of Biomedicine