Abstract Details

Poster 55: Regulatory Mechanisms and Pharmacological Control of Epileptic Seizures in Zebrafish

Simon Hand1, Val Gillet2, Joseph Harrity3, Vincent Cunliffe1
1Department of Biomedical Science, University of Sheffield, Sheffield S10 2TN
2Information School, University of Sheffield, Sheffield S1 4DP
3Department of Chemistry, University of Sheffield, Sheffield S10 2TN
Epilepsy is a disorder of the nervous system in which patients exhibit marked vulnerability to recurrent, unprovoked bouts of excessive or hypersynchronous neuronal activity in the brain, which are known as seizures. Although many people with epilepsy respond satisfactorily to anti-epileptic drugs (AEDs), around 30% of patients do not respond to the available first-line treatments. There is, therefore, a significant unmet clinical need for better understanding of the disease process in order to develop new anti-epileptic drugs.

The aim of this project is to develop novel lead compounds with established genetic and molecular targets, which can facilitate the development of better AEDs. The project utilises the in vivo screening developed within the Centre for Developmental and Biomedical Genetics to experimentally explore the anticonvulsant effects of target-focused chemical libraries. Zebrafish embryos have been shown to provide a reliable epileptic seizure model to identify new anti-epileptic compounds.

We have tested the hypothesis that kinase inhibition is a valid anticonvulsant strategy by the screening of over 1000 kinase inhibiting compounds. 42 kinase inhibitors have been identified as novel anticonvulsants, however, the specific therapeutic targets of these hits within the kinome are still unknown. Identification of these targets, and thus, mechanisms of action are currently being investigated using a combination of in vivo and in silico techniques. Initial work has focused on prediction of inhibition of specific kinases by comparing the Shannon entropy descriptor (SHED) profile of each compound and respective binding sites. SHED profiling is a low dimension description of hydrophobicity, aromatic, and hydrogen bond accepting or donating areas of a molecule. Results revealed little overlap between the targets predicted for each hit, indicating that although the screened compounds are effective inhibitors of the kinome the targets are not well defined. Future work will focus on docking the most potent hit compounds into a range of available structures of potential kinase targets. The predicted interactions will be quantified and compared in order to elucidate the likely targets which are being inhibited in vivo. Those compounds which are predicted to be the most potent novel structures in silico will be synthesised and screened.

1. S. Baxendale, C. J. Holdsworth, P. L. Meza Santoscoy, M. R. M. Harrison, J. Fox,C. A. Parkin, P. W. Ingham, and V. T. Cunliffe, Disease Models & Mechanisms, 2012, 01009, 1-12.
2. S. C. Baraban, M. R. Taylor, P. A. Castro, and H. Baier, Neuroscience, 2005, 131, 759-768
3. F. M. Areias, J. Brea, E. Gregori-Puigjanéc, M. E. A. Zaki, M. A. Carvalhoa, E. Domínguez, H. Gutiérrez-de-Teránb, M. F. Proençaa, M. I. Loza and J. Mestres, Bioorganic & Medicinal Chemistry, 2010, 18, 3043-3052

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