Flagship: Cellular decision making

Cellular decision making

• 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.

  The emphasis here is 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. Systems pharmacology of these vGPCRs in relation to HCMV-associated diseases like cancer are currently a fast evolving area of focus.

  In addition to 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

  Fragment-based approaches are ideal for academic and 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.

  Both pharmacological screening and alternative fragment screening technologies are being explored such as in silico docking, SPR screening, NMR and X-ray analysis. These screening technologies are developed in close ollaboration with various 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.

  Phosphodiesterases (PDEs) are  relevant in combating neglected diseases (e.g African sleeping disease) as well as in antimicrobials research where currently multiple are currently under investigation using multidsiciplinairy drug discovery approaches.

• Areas of application

  Over the years several start-ups in the pharma-biotech space were established including Griffin Discoveries, De Novo Phamaceuticals and Griffin;  a variety of patents are available for licensing.

• Use case

  Radio Nucleide Centre (Bert Windhorst) autologues transplantation, or lama antibodies (indien patent is toegekend).

• Collaborations

  Continued collaboration in AIMMS with Iwan de Esch in fragment based drug discovery (FBDD) , Tom Grossman in peptide modelling, Eelco Ruijter in organic synthesis and Daan Geerke in modelling. Programs participated in include Top Institute Pharma, Technology Foundation STW, EU-FP7, European Medicines Initiative (IMI) and FRAGNET.