QSAR - quantitative structure activity relationship
Neuroactive substances can be well studied with neuronal network cultures on microelectrode arrays. It is possible to establish a very
precise high content profile of action for neuroactive substances. Dose response curves for significant and relevant spike train
parameters are used to characterize interesting action profiles. These dose response curves have excellent properties.
For all investigated anticonvulsive substances, we compared
the quoted therapeutic ranges from literature with our EC10 and EC50 of spike rate and
found a high rate of coincidence. Furthermore neuronal cell cultures on microelectrode arrays show an extraordinary sensitivity as
biosensors with a wide dynamical range. For example, for diazepam we can observe differences in the course of the spike rate
over 6 orders of
magnitudes. Our data are reproducible with a small standard deviation. Finally, spike train data of neuronal network cultures provide
extensive information describing neuronal activity. For these reasons neuronal network cultures are extremely well suited to
combine this method with in silico screening in virtual compound libraries with QSAR, quantitative structure activity relationship and
homology screening to discover new lead compounds and drug candidates.
In cooperation with OntoChem GmbH we combined their
newly developed chemical descriptors (ToTo's - topological torsions on base of SMILES, simplified molecular input line entry system) with our pattern recognition algorithms to search for neuroactive
substances in combinatorial chemistry and to synthesize new CNS drug candidates with multicomponent reactions. These methods have been very successfully tested for known combinatorial chemistry libraries.
With the help of these virtual screening methods in compound libraries, multi component reaction methods from combinatorial chemistry
and a precise characterization of synthezid substances we can deliver in cooperation with our partners lead compounds with a
precise and well defined action profile on these neuronal network cultures.
We have experience with the following receptors:
- GABA-A receptor, benzdiazepine binding site and steroid binding site
- GABA-B receptor
- NMDA - receptor
- and other GPCR, G-Protein coupled receptors, as mGluR.
