Reference : Combined experimental and computational approaches to study the action of blockers of sm...
Scientific congresses and symposiums : Paper published in a journal
Engineering, computing & technology : Computer science
Human health sciences : Pharmacy, pharmacology & toxicology
http://hdl.handle.net/2268/83965
Combined experimental and computational approaches to study the action of blockers of small conductance calcium-activated potassium (SK) channels
English
Dilly, Sébastien mailto [Université de Liège - ULg > Département de pharmacie > Chimie pharmaceutique > >]
Lamy, Cédric mailto [Université de Liège - ULg > Département des sciences biomédicales et précliniques > Pharmacologie > >]
Liégeois, Jean-François mailto [Université de Liège - ULg > Département de pharmacie > Chimie pharmaceutique >]
Seutin, Vincent mailto [Université de Liège - ULg > Département des sciences biomédicales et précliniques > Pharmacologie >]
2010
Acta Physiologica Scandinavica
Blackwell Publishing
199
supplement 678
O-10
No
No
International
0001-6772
1365-201X
Oxford
United Kingdom
Belgian Society for Fundamental and Clinical Physiology and Pharmacology, Spring Meeting 2010
27/03/2010
Belgian Society for Fundamental and Clinical Physiology and Pharmacology
Namur
Belgium
[en] Small conductance calcium-activated potassium channels (SK) are widely expressed throughout the central nervous system (CNS) and underlie medium duration afterhyperpolarizations in many types of neurons. Three subtypes of SK channels, SK1, SK2 and SK3, have been identified so far in different parts of the brain. Blocking SK channels might be beneficial in the treatment of several CNS disorders such as depression, Parkinson’s disease and cognitive disorders.
Until now, the precise site of interaction between these channels and their blockers has not yet been elucidated. In this context, molecular modeling is a theoretical approach that can quickly provide ideas on the binding mode of SK blockers. We first performed homology modeling of the S5-H5-S6 portion of the channels on the basis of the crystal structure of the KcsA potassium channel (Zhou et al. Nature. 2001, 414, 43-48). The binding sites of N-methyl-laudanosine (NML) (Scuvée-Moreau et al. J. Pharmacol. Exp. Ther. 2002, 302, 1176-83), a non-selective and non-peptidic ligand, and apamin (Blatz et al. Nature. 1986, 323, 718-20), an octadecapeptide with a preference for the SK2 subtype, were subsequently explored by docking analysis. Different amino-acids were suggested to interact with the two blockers. The docking of NML revealed a binding site in the turret region, far from the pore. The docking of apamin identified a very large binding site that includes a portion of the site of NML. In order to confirm the predicted binding sites, site-directed mutagenesis was used. The first mutant channels tested in electrophysiological experiments by the patch clamp technique validated some of the theoretical data. Using this strategy, we hope to get a better understanding of the mechanism of action of SK blockers and eventually find strategies to obtain subtype-selective blockers.
Laboratory of Pharmacology and GIGA-Neurosciences ; Laboratory of Medicinal Chemistry, Drug Research Center
University of Liège
Researchers ; Professionals ; Students
http://hdl.handle.net/2268/83965
http://www.blackwellpublishing.com/aphmeeting/abstract.asp?MeetingID=770&id=86176&meeting=APSABS2010678

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