TNF interactions

Combined use of NMR and DNA encoded libraries for drug discovery

Molecular interactions are key processes in biology, chemistry and medicine. The challenging identification and structural characterization of interacting molecules provides the basis for a detailed understanding of these processes. In this research we want to investigate the potential of the combination of two techniques which are so far applied separately in drug discovery: NMR spectroscopy in solution and DNA-encoded chemical libraries (DECL). NMR provides structural and dynamic data on molecular interactions whereas DECL can efficiently identify ligands that bind to a particular protein. Whereas DECL delivers weak binders relatively easily, the optimization for specific and tight binding becomes more involved. The search process by DECL could be guided by structural and dynamic data that is obtained from NMR measurements in solution. The detailed procedures on how to combine the two techniques to reach this goal efficiently shall be established within this study.

For the development of procedures for a combined use of NMR and DECL in drug discovery we will search drug candidates for the tumor necrosis factor alpha (TNF-a) and other drug targets. TNF-a is related to many human diseases and is a major target in pharmaceutical research in industry and universities. So far, only large antibody based molecules are available that inhibit TNF-a. With the combination of NMR and DECL we want to identify a small compound that tightly and specifically binds TNF-a. In a first step, drug candidates will be identified by DECL with a library developed by the co-applicant. The hits will be tested by in-vivo assays and the binding site will be structurally and dynamically characterized by NMR measurements.

The outcome of this work will make available a novel procedure that combines NMR and DECL for efficient drug discovery. Specifically, our results will provide a better basis for further rational improvements of small molecules blocking TNF-a activity and possibly deliver a drug candidate for TNF-inhibition.

Supported by

Schweizerischer Nationalfonds (SNF)

In collaboration with

Dr. Jörg Scheuermann, Daniela Hofmann