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