Division of Medicinal Chemistry

Rob Leurs        Martine Smit        Iwan de Esch

Prof. Dr. Rob Leurs           Prof. Dr. Martine Smit        Prof. Dr. Iwan de Esch

The research mission of the Division of Medicinal Chemistry is to obtain detailed molecular understanding of the binding and the mechanism of action of biologically active molecules. The division uses an integrated research approach which combines design, synthesis, pharmacological and biochemical characterization of biologically active molecules. Emerging scientific concepts such as chemogenomics, molecular signaling networks, ligand-biased signalling and the thermodynamic and kinetic aspects of ligand-protein binding are currently being investigated. Advances in these fields will lead to more efficient and rational drug discovery. We focus on two research lines, G protein-coupled receptors (GPCRs) and Fragment-Based Drug Design (FBDD). The interface of these research lines - structure-based FBDD in the field of GPCRs - is a major scientific challenge.

G-protein-coupled receptors (GPCRs)

GPCRs are one the most successful drug targets to date and remain an important focus point in modern drug discovery.

The division undertakes the design and synthesis of new ligands for several GPCRs, like the histamine receptors H1, H3 and H4 as well as chemokine receptors CXCR3, CXCR4 and CXCR7. We have obtained detailed understanding of the action of selected ligands by combining modern molecular pharmacological concepts (e.g. allosteric modulation, dimerization, inverse agonism, ligand-biased signaling and signalling networks), receptor mutagenesis and computational modeling.

We have a specific emphasis on virally encoded GPCRs (vGPCRs). The division is leading in the molecular characterization of the human cytomegalovirus (HCMV)-encoded vGPCRs and their role in redirecting cellular signaling networks. Currently, we have directed this research focus to the understanding of the systems pharmacology of these vGPCRs in relation to HCMV-associated diseases like cancer.

Besides small ligands targeting GPCRs, nanobodies (llama-derived antibodies) have been generated targeting above-mentioned GPCRs. These GPCR-targeting nanobodies serve as attractive research tools to modulate and monitor (viral) GPCR function.

Fragment-Based Drug Design

Moreover, the Division of Medicinal Chemistry is focusing on structure-based drug design, and in particular on Fragment-Based Drug Design (FBDD). Fragment-based approaches are ideal for academic and small biotech drug discovery efforts, as these technologies are design-intensive rather than resource-intensive. We have established a fragment library containing 1500 low molecular weight compounds. Currently, this library is effectively used as a starting point to develop ligands against a variety of targets: GPCRs, kinases, ligand-gated ion channels, protein-protein interactions, etc.

Next to pharmacological screening, alternative fragment screening technologies are being explored such as in silico docking, SPR screening, NMR and X-ray analysis. The usage of these screening technologies is performed in collaboration with diverse research institutes and pharmaceutical companies. Targets include acetylcholine binding protein (AChBP), a structural homolog of the ligand-binding domain of cys-loop receptors (e.g. nicotinic acetylcholine-, serotonin 5HT3- and GABA receptors), tyrosine kinases, protein-protein interactions, phosphodiesterases and GPCRs.

In addition, phosphodiesterases (PDEs) relevant in combating neglected diseases (e.g African sleeping disease) and antimicrobials are important targets which are currently under investigation using multidsiciplinairy drug discovery approaches.

Subgroups

The following subgroups are associated with these chairs:

Chris de Graaf              Marco Siderius              Henry Vischer       

Dr. Chris de Graaf                    Dr. Marco Siderius                 Dr. Henry Vischer
Computational Medicinal         Receptor Biochemistry            Molecular Pharmacology
Cchemistry

Maikel Wijtmans              Bert de Boer-

Dr. Maikel Wijtmans                 Dr. Bert de Boer
Synthetic Medicinal                  Biochemistry
Chemistry