Biomedical Engineering Reference
In-Depth Information
6 Conclusions
Within this review, we presented ligand-based and structure-based approaches to
predict the potential risk of compounds for binding to the hERG potassium channel
in a strength, which might lead to Torsades de Points. Although numerous studies
have been conducted and most of them exhibit good to excellent predictivity, this
issue still is not completely resolved. QSAR studies definitely suffer from the small
chemical space the training compounds are covering, which renders generalization
of the models difficult. Although pharmacophore models and docking could over-
come this general drawback of QSAR approaches, they very often do not take into
account the plasticity of the channel. Finally, channel opening and closing is
a dynamic process and interaction with drugs can occur at any step. Thus, in
an industrial setup, high throughput biological testing and repeated lead optimiza-
tion cycles are still the method of choice to get rid of unwanted hERG activity.
Finally, there is increasing evidence that, in addition to hERG, other cardiac ion
channels are involved in TdP. Thus, prediction of the final clinical outcome on the
organismic level will require integrated approaches, as for example, pursued by
large EU-projects such as the Virtual Physiological Human Network of Excellence
(
http://www.vph-noe.eu
) or the eTox project, which aims at prediction of the
toxicological profiles of small molecules in early stages of the drug development
pipeline (
http://193.146.190.66/etox-web/index.html
).
Acknowledgments Andrea Schiesaro is grateful for financial support by the University of
Vienna under the framework of the PhD program “Molecular Drug Target” and for support
from the Innovative Medicines Initiative (eTox, 115002).
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