Modulation of G-protein coulped receptors (GPCRS)

G protein-coupled receptors, also known as seven-transmembrane domain receptors (7TMRs), are instrumental in cellular communication as they convert extracellular stimuli into intracellular responses. Not surprisingly, these receptor proteins are by far the most rewarding class of drug targets. In 2012 the Nobel Prize of Chemistry was awarded to professors Lefkowitz and Kobilka for their breakthroughs in this research field.

GPCRsRob Leurs: “The discoveries that 7TMRs can be modulated in different ways has resulted in the insight that molecular understanding of these proteins can still be much improved”. With the TOP-PUNT grant 7 ways to 7TMR modulation, Leurs, Smit and other staff members aim to provide an integrative view of 7TMR structure and function and to devise new molecular tools to study and modulate 7TMRs.

New understanding
Their upcoming studies have a multidisciplinary approach and include fragment-based drug discovery, kinetics of ligand-protein binding and specific modulation of cellular signaling networks. This will lead to new understandings how 7TMRs work on a molecular level. One way to modulate a receptor is by biased ligands, which selectively enable a certain signal transduction pathway through a 7TMR that can active several possible downstream pathways.

These insights will enable the research community to more efficiently and more specifically modulate 7TMRs which will lead to a new generation of medicines with improved therapeutic effects. Leurs: “This offers new venues for drug discovery, since such precise molecular interventions will minimize the risk of adverse side effects.”

National center of excellence
Medicinal Chemistry at VU University of Amsterdam has been recognized as one of the national centers of excellence in chemistry in the Sector Plan Physics and Chemistry. The center has since been strengthened with the appointments of Iwan de Esch as professor in Biocomputational Chemistry for Drug Innovation and Daan Geerke as assistant professor in Molecular and Computational Toxicology. Earlier, NWO awarded three major grants to the Medicinal Chemistry center: a VICI (Martine Smit), a TOP (Romano Orru) and an ECHO (Iwan de Esch).

TOP-PUNT grant

Rob Leurs en Martine Smit
Rob Leurs and Martine Smit, professors of the Medicinal Chemistry and Target & Systems Biochemistry research groups resp. together receive a TOP-PUNT grant of €2 million from NWO to continue their research on G protein-coupled receptors.
TOP-PUNT grants are meant for small teams of 2 or 3 professors appointed at chemical centers of excellence and conducting influential research in their field. The professors can use the grant to jointly set up, strengthen or renew challenging and innovative lines of research. In 2014, 4 TOP-PUNT grants were awarded.

"The grant is a recognition for our many years of excellence in this field," claims Martine Smit. "Also in the cooperation envisaged between the Amsterdam Institute for Molecules, Medicines and Systems of the VU and research groups within the Swammerdam Institute for Life Sciences of the University of Amsterdam and VU Medical Center, we are now able to further strengthen this line of research."