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Rehabilitation Studies for withdrawn drugs from the market: derivation of non-hERG1 channel blocker cisapride analogues using multi-faceted approaches

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http://pubman.mpdl.mpg.de/cone/persons/resource/persons86621

Durdagi,  Serdar
Molecular Simulations and Design, Max Planck Institute for Dynamics of Complex Technical Systems, Max Planck Society;

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Citation

Durdagi, S., Randal, T., Duff, H. J., & Noskov, S. Y. (2013). Rehabilitation Studies for withdrawn drugs from the market: derivation of non-hERG1 channel blocker cisapride analogues using multi-faceted approaches. Poster presented at 57th Biophysical Society Meeting, Philadelphia, USA.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0013-87C0-0
Abstract
The human ether-a-go-go related gene 1 (hERG1) potassium ion channel is a key element for the cardiac delayed rectified potassium current IKr and it plays an important role in the normal repolarization of the action potential. Diverse types of organic compounds used both in common cardiac and noncardiac medications can reduce the IKr and may lead to ventricular arrhythmia. Therefore, several approved drugs have been withdrawn from the market because of their effects on QT interval prolongation. Since most of these drugs have high potency for their principal targets, rehabilitation studies for decreasing their high hERG1 blocking affinities while keeping them active at the binding site of their targets may lead re-use of these drugs. For this aim, a gastroprokinetic agent, cisapride, is studied. Cisapride is withdrawn from the market because of its high hERG1 blocking affinity. In this study, analyses of fragment interactions of cisapride at the human A2A adenosine receptor and hERG1 central cavities is investigated using in silico applications (molecular docking, molecular dynamics simulations, de novo drug design) and novel and safer (with low hERG1 blocking affinities) of cisapride derivatives are proposed for their synthesis and their biological tests.