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Research

Our group focuses on the design, synthesis and biological testing of small molecules that can modulate the activity of a specific target playing a crucial role in a human disease. The results of the biological evaluation and X-ray-crystallographic studies of the first candidates are incorporated into further optimization strategies, not only in terms of affinity but also taking pharmacokinetic properties into account. If no structural information is available, computer-aided drug design (CADD), also in collaboration with other research groups, or ligand-based approaches are pursued as an alternative.

We primarily synthesize small molecule libraries tailored to a target using both classical and modern organic chemistry. These small molecules are tested for biological activity in our own or in collaboration with other research groups and optimized in further design cycles. Using protein X-ray crystallography, we determine the ligand binding modes to support structure-based optimization.

Kinases

Kinases belong to the class of transferases and catalyze the transfer of phosphate groups from adenosine triphosphate (ATP) to specific substrates. While oncology is the most important application area for small molecule kinase inhibitors, there are also several areas and research interests in immunology and beyond.

In our research group, we focus on the design and synthesis of novel Pim-1 and Protein Kinase A (PKA) kinase inhibitors. Their in silico design is carried out both internally and in collaboration with other research groups. The subsequent synthesis, in-vitro activity tests and determination of the X-ray crystal structure enable further design cycles.

Nuclear Receptors

Peroxisome proliferator-activated receptors (PPARs) belong to the family of nuclear receptors and are a promising target in drug research. Diseases such as type 2 diabetes mellitus, hyperlipidemia or the metabolic syndrome are among the areas of indication, as well as inflammatory diseases such as rheumatoid arthritis.

Our research focuses on the development of selective PPARβ/δ inhibitors based on new basic structures. In cooperation with other research groups, these ligands are investigated with regard to their affinity and corepressor recruitment and further developed based on these results, with the main aim of optimizing the pharmacokinetic properties of these ligands to enable their use in complex model systems, such as rodents.

GPCRs

G protein-coupled receptors (GPCRs) are transmembrane receptors with numerous physiological roles such as several senses, immunological and automatic nervous system regulation. GPCR-targeting ligands are long-established and crucial drug-targets in nowadays medicine.

Within the scope of a multidisciplinary project regarding GPCR ligands for underexplored Epitopes (GLUE), our research group engages in the chemical synthesis of such in silico-designed ligands and their optimization especially for FFAR, GPRC5B and Endothelin receptors.

Transporters

The solute carriers are a large protein family and comprise about 400 members. We are particularly interested in the SLC10 class, which includes NTCP, ASBT and SOAT. NTCP and ASBT play an important role in the circulation of bile acids whereas SOAT transports sulfated steroids. NTCP also serves as an entry point for the hepatitis B virus.

Matrix Proteins

VP40 is the matrix protein of the filovirus and has various functions in the viral replication cycle. It is responsible for the budding of new virions and down-regulates the viral genome and transcription, thus making it an interesting and promising target for small molecules. 

In our research group we are working on the development and synthesis of novel VP40 inhibitors. The determination of their biological value and X-ray crystallography are carried out in collaboration with other research groups. 

PROTACs

Proteolysis targeting chimeras (PROTACs) are bifunctional molecules linked together by a variable linker. One part of the molecule binds to the protein of interest (POI), the other is an E3 ubiquitin ligase-targeting molecule. By recruiting an E3 ubiquitin ligase, the POI is targeted for subsequent degradation by the proteasome. PROTACs have the advantage that their POI-binding domain does not have to inhibit the activity of the POI, but only needs to bind to it with high selectivity.

We are currently working on antiviral PROTACs against MPro of SARS-CoV-2. The aim is to develop PROTACs for antiviral target molecules and thus establish new active substances in this area.

Temporary covalent fragment-based drug design

Temporary covalent fragment-based drug design (TCFBDD) is a new approach in the discovery of novel active small molecules. Starting point is a non-binding, low active fragment. This fragment is to be merged with a covalent anchor, which enables optimization via X-ray crystallography. Objective of this study is to grow a fragments affinity towards its target until a covalent anchor is not needed anymore to bear a binding mode within a crystal structure.

In our research group we are currently working on the development of this novel approach in drug design utilizing a model protein.

For further information:

Prof. Dr. Wibke Diederich
Institut für Pharmazeutische Chemie und
Zentrum für Tumor- und Immunbiologie (ZTI)
Philipps-Universität Marburg
Hans-Meerwein-Straße 3
35043 Marburg
Germany

tel.: +49-6421-28-25810
fax: +49-6421-28-28994
email*: wibke.diederich@staff

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