Drugging conformational states of GPCRs

Published on February 25, 2021   41 min

Other Talks in the Series: G Protein-Coupled Receptors (GPCRs) Signaling in Health and Disease

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Hi, my name is Peter Kolb. I'm from Philipps-University in Marburg, the Department of Pharmaceutical Chemistry. Today, I'm going to speak about drugging conformational states of GPCRs. I'm going to showcase a few things that we have done over the past years, that highlight the importance of addressing the appropriate conformation of a G protein-coupled receptor.
Before I go into the research, let me show you some of the people who have been contributing to this research, most importantly Florent Chevillard, but I'm also going to show you research by Dennis Schmidt and things that we have done in collaboration with Jillian Baker at Nottingham University, and also Brian Kobilka at Stanford University, and a little bit of research that we have done with Nuska Tschammer at Friedrich-Alexander-University in Erlangen.
I'm showing you a word cloud that exemplifies the research that we're doing. You can see that receptors and G protein-coupled receptors (GPCRs) are our most investigated targets. We are trying to find ligands and inhibitors for these receptors, agonists, inverse agonists, and antagonists. We are trying to get more into the chemical space to find novel compounds, novel molecules, that might have novel effects and modulatory effects on the receptors and proteins in general.
This is my cartoon representation of what structure-based ligand discovery is. We have a protein (this is the box) that has binding pockets, which are the holes in this box that you can see. We have little blocks of different shapes, and we try to find the block with the corresponding shape for a particular binding pocket. Why is this something that you don't do in kindergarten any more? The answer is that both the box as well as the blocks that we have, change their shape so they are flexible. Plus, we have in the order of tens of millions of blocks that we can try to fit into any given binding pocket, so this becomes a fundamentally harder problem.