-Structure Prediction:

Diazepam bound to its binding site at the GABA_A receptor ? finally in 3D. On the basis of crystal structures of less complex relatives of the GABAA receptor, we have computed thousands of hypothetical structures of diazepam (Valium) bound to the high affinity benzodiazepine binding site. Using an innovative workflow we selected the "best" models and used them to identify new ligands that were proven experimentally to bind. The results have been published in Nature Chem Biol, 8: 455-464, 2012.

Currently we work on the bound state structures of more ligands, and on additional receptor subtypes.

 - Understanding modulatory binding sites:

 Many allosteric modulators of GABA_A receptors act at binding sites that have not yet been identified on the protein complex. Using biochemical and pharmacological approaches, we search for binding sites. Recently we have shown that some pyrazoloquinolinones, such as the compound CGS 9895, act as allosteric modulators at a binding site located the α+β- interface, in a manner very similar to the action of benzodiazepines.  This has been published 2011 in J Neurosci, 31: 870-877. More of this work appeared in 2012 in the Br. J. Pharmacol.

Currently we work on understanding the structure of subtypes with sufficient accuracy to be able to predict subtype selective ligands. We continue to integrate experimental data into our structure predictions.

-Subtype seletive ligands for the α+β- bindingsite:

After we first described positive modulation similar to benzodiazepine action occurring at the α+β- binding site we explored this phenomenon in a wide range of receptor subtypes and with more than 30 test compounds. We identified a ligand with exquisite selectivity for the α6β3γ2 subtype which occurs in the cerebellum and in ganglia, and may be involved in important physiological processes. Furthermore we identified ligands that modulate α1β3δ receptors with super-efficacy by binding to the α1+β3- interface. These findings have been published 2013. Follow up work is underway.

We continue to study this exciting binding site as a prospective drug target, and to identify selective ligands for it together with collaboration partners from medicinal chemistry and pharmacoinformatics.

Ramerstorfer et al (2011) J Neurosci 31:870
Richter et al (2012) Nat Chem Biol (online)
Sieghart et al (2012) Brit J Pharmacol 166:476
Varagic et al. (2013a) Br. J. Pharmacol 169(2):371-83
Varagic et al. (2013b) Br. J. Pharmacol 169(2): 384-99
Mirheydari et al. (2013) Neurochem Res. 2013 Sep 26
Middendorp et al. (2014) ACS Chem Biol. 2014 Jun 27. [Epub ahead of print]