Identification of drug targets related to the induction of ventricular tachyarrhythmia through a systems chemical biology approach

Toxicological Sciences : an Official Journal of the Society of Toxicology
Sergey M IvanovV V Poroĭkov

Abstract

Ventricular tachyarrhythmia (VT) is one of the most serious adverse drug reactions leading to death. The in vitro assessment of the interaction of lead compounds with HERG potassium channels, which is one of the primary known causes of VT induction, is an obligatory test during drug development. However, experimental and clinical data support the hypothesis that the inhibition of ion channels is not the only mechanism of VT induction. Therefore, the identification of other drug targets contributing to the induction of VT is crucial. We developed a systems chemical biology approach for searching for such targets. This approach involves the following steps: (1) creation of special sets of VT-causing and non-VT-causing drugs, (2) statistical analysis of in silico predicted drug-target interaction profiles of studied drugs with 1738 human protein targets for the identification of potential VT-related targets, (3) gene ontology and pathway enrichment analysis of the revealed targets for the identification of biological processes underlying drug-induced VT etiology, (4) creation of a cardiomyocyte regulatory network (CRN) based on general and heart-specific signaling and regulatory pathways, and (5) simulation of changes in the behav...Continue Reading

References

Mar 23, 2000·Cardiovascular Research·G Z Feuerstein, P R Young
Aug 2, 2007·Journal of Cardiovascular Electrophysiology·Andrew H SmithPrince J Kannankeril
Mar 4, 2008·SAR and QSAR in Environmental Research·O FilzV Poroikov
Jun 4, 2008·Cardiovascular Research·Nicholas J SeversStephen Rothery
Oct 15, 2008·SAR and QSAR in Environmental Research·A KelE Wingender
May 13, 2009·Journal of Chemical Information and Modeling·Josef ScheiberJeremy L Jenkins
Oct 8, 2009·Circulation. Arrhythmia and Electrophysiology·Augustus O Grant
Oct 8, 2009·Circulation. Arrhythmia and Electrophysiology·Andreas S Barth, Gordon F Tomaselli
Dec 22, 2009·SAR and QSAR in Environmental Research·O N KoborovaV V Poroikov
Jan 21, 2010·Molecular Systems Biology·Michael KuhnPeer Bork
Mar 10, 2010·Current Drug Safety·Marcelo Luis PonteGuillermo Di Girolamo
Mar 13, 2010·Current Pharmaceutical Design·Alexey LaguninVladimir Poroikov
Apr 22, 2010·Science Signaling·Seth I BergerRavi Iyengar
Jul 14, 2010·Cardiovascular Research·David A Brown, Brian O'Rourke
Nov 19, 2011·Europace : European Pacing, Arrhythmias, and Cardiac Electrophysiology : Journal of the Working Groups on Cardiac Pacing, Arrhythmias, and Cardiac Cellular Electrophysiology of the European Society of Cardiology·Constantinos O'MahonyPerry Elliott
Nov 28, 2012·Experimental Physiology·Kwanghyun SohnBonnie B Punske
Dec 1, 2012·Nature Reviews. Drug Discovery·Joanne BowesSteven Whitebread
Mar 12, 2013·Naunyn-Schmiedeberg's Archives of Pharmacology·László DrimbaBarna Peitl
Apr 6, 2013·Pharmacology & Therapeutics·Kathy C G de GitMarcel A G van der Heyden
Apr 6, 2013·Circulation. Arrhythmia and Electrophysiology·Ali A SovariSamuel C Dudley
Apr 27, 2013·Drug Safety : an International Journal of Medical Toxicology and Drug Experience·Rashmi R ShahDevron R Shah
May 2, 2013·Molecular Systems Biology·Michael KuhnPeer Bork
Jun 5, 2013·Toxicology and Applied Pharmacology·Junnat HamdamChristopher Goldring
Jan 1, 2014·American Journal of Physiology. Heart and Circulatory Physiology·Angelica Lopez-IzquierdoMartin Tristani-Firouzi
Mar 15, 2014·Circulation Research·Mark J Shen, Douglas P Zipes

❮ Previous
Next ❯

Related Concepts

Related Feeds

Arrhythmia

Arrhythmias are abnormalities in heart rhythms, which can be either too fast or too slow. They can result from abnormalities of the initiation of an impulse or impulse conduction or a combination of both. Here is the latest research on arrhythmias.