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Medicinal Chemistry

The research mission of Medicinal Chemistry is to obtain detailed molecular understanding of the binding and the mechanism of action of biologically active molecules.

Medicinal chemistry integrates the design, synthesis, and characterization of biologically active molecules, exploring novel concepts like chemogenomics and molecular signaling networks for more efficient drug discovery. Our focus lies on G protein-coupled receptors (GPCRs) and Fragment-Based Drug Design (FBDD), particularly the challenging structure-based FBDD for GPCRs.

Prof. Dr. Martine Smit, full Professor Target and Systems Biochemistry        
Prof. Dr. Iwan de Esch, full Professor Drug Design & Synthesis
Prof. Dr. Rob Leurs, full Professor      

Medicinal Chemistry consists of two research lines:

G Protein-Coupled Receptors (GPCRs)
GPCRs represent one of the most successful drug targets to date, remaining pivotal in modern drug discovery. We concentrate on designing and synthesizing new ligands for various GPCRs, including histamine receptors H1, H3, and H4, and chemokine receptors CXCR3, CXCR4, and CXCR7. By integrating modern molecular pharmacological concepts like allosteric modulation and receptor mutagenesis, we have gained profound insights into ligand functioning. Special attention is given to viral-encoded GPCRs (vGPCRs), particularly focusing on the molecular characterization of human cytomegalovirus (HCMV) encoded vGPCRs, exploring their role in redirecting cellular signaling networks, and understanding their systemic pharmacology in relation to HCMV-associated diseases such as cancer. In addition to small ligands, we also generate GPCR-targeted nanobodies derived from llama antibodies, promising tools for modulating viral and cellular GPCR functions.

Fragment-Based Drug Design (FBDD)
Medicinal chemistry emphasizes structure-based drug design, notably FBDD. Fragment-based approaches are cost-effective and highly design-efficient, making them ideal for academic and small biotech drug discovery endeavors. We have established a fragment library comprising 1500 low-molecular-weight compounds, serving as a starting point for ligand development against various targets, including GPCRs, kinases, and protein-protein interactions. Apart from pharmacological screening, we explore alternative fragment screening technologies such as in silico docking, SPR screening, NMR, and X-ray analysis. These endeavors, conducted in collaboration with various research institutes and pharmaceutical companies, target proteins like acetylcholine binding protein (AChBP), tyrosine kinases, phosphodiesterases, and GPCRs. Key targets also encompass phosphodiesterases (PDEs) relevant in combating neglected diseases like African sleeping sickness and antimicrobial agents, employing multidisciplinary drug discovery methods.

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Our team

Do you want to know more?

Feel free to contact us.

Prof. Dr. Martine Smit -

Prof. Dr. Iwan de Esch -

Vrije Universiteit Amsterdam
Department of Chemistry and Pharmaceutical Sciences
De Boelelaan 1108
1081 HZ Amsterdam