Division of Medicinal Chemistry

Research profile

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 accomplishes that with 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)

G-protein-coupled receptors (GPCRs)

We focus on two research lines: GPCRs and structure-based drug design. The interface of these research lines - structure-based drug design in the field of GPCRs - is a major scientific challenge. GPCRs are one the most successful drug targets to date and remain an important focus point in modern drug discovery.

The division develops new ligands for several of the recently discovered GCPRs, like histamine receptors H3 and H4 and chemokine receptors CXCR3 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 charaterization 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.

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 biotechmologic drug discovery efforts, as these technologies are design intensive. We have established a fragment library containing 1200 low molecular weight compounds. Currently, this library is effectively used 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: insilico docking, SPR screening, NMR and X-ray analysis. The usage of these screening technologies are performed in collaboration with diverse research institutes and pharmaceutical companies. Targets include acetylcholine binding protein (AChBP) as 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.


The following subgroups are associated with these chairs: