Division of Medicinal Chemistry

Research profile

Prof. dr. Rob Leurs	Prof. dr. Martine Smit

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, by means of an integrated approach combining design, synthesis, pharmacological and biochemical characterization. Molecular insights are important to enable more efficient rational drug discovery approaches.

Research lines

We focus on two research lines, namely G-protein-coupled receptors (GPCRs), and structure-based drug design. The interface to these research lines, namely structure-based drug design in the field of GPCRs is seen as 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 histamine (H3 and H4 receptors) and CXC chemokine receptors (CXCR3 and CXCR7). Moreover, detailed understanding of the action of selected ligands is obtained by combining modern molecular pharmacological concepts (e.g. allosteric modulation, dimerization, inverse agonism), receptor mutagenesis and computational modeling.
Specific emphasis is given to the group of virally encoded GPCRs (vGPCRs).  The division is leading in the molecular charaterization of especially the human cytomegalovirus (HCMV)-encoded vGPCRs and their role in redirecting cellular signaling networks. Currently, the focus is directed towards an understanding at the Systems Pharmacology of these vGPCRs in relation to HCMV-associated diseases as e.g. cancer.

Fragment based Drug Design

Recently the division is focusing strongly on structure-based drug design (SBDD), and in particularly on the emerging Fragment-Based Drug Design (FBDD). Especially fragment-based approaches are ideal for academic and small biotech drug discovery efforts as these technologies are design intensive. We have established a diverse fragment library containing 1200 low molecular weight compounds, which is currently effectively used to develop ligands against a variety of targets (GPCRs, kinase, ligand-gated ion channels, protein-protein interactions, etc). Next to pharmacological screening, alternative fragment screening technologies are being explored, e.g., in silico docking, SPR screening (collaboration with Dr. Helena Danielson, Beactica, Sweden and section Biomolecular Analysis of Prof. Irth c.s.), NMR (collaboration Leiden University, Dr. Siegal) and X-ray analysis (collaboration prof. Sixma, NKI and prof. Smit FALW-VU). Targets include Acetylcholine Binding protein (AChBP) as structural homolog of the ligand-binding domain of Cys-loop receptors (in particular nicotinic acetylcholine-, serotonin 5HT3- and GABA receptors), tyrosine kinases, protein-protein interactions and GPCRs.

The following subgroups are associated with this chair:

Dr. Iwan de Esch: Design and Synthesis;
Dr. Jacqueline van Muijlwijk-Koezen.

Dr. Marco Siderius: Receptor Biochemistry;
Dr. Henry Vischer: Molecular Pharmacology.

Dr. Chris de Graaf: Computational medicinal chemistry
Dr. Maikel Wijtmans: Synthetic medicinal chemistry

Detailed information can be found in the department's latest progress report.