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

Sergey M Ivanov; Alexey A Lagunin; Pavel V Pogodin; Dmitry A Filimonov; Vladimir V Poroikov

doi:10.1093/toxsci/kfv054

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

Toxicol Sci. 2015 Jun;145(2):321-36. doi: 10.1093/toxsci/kfv054. Epub 2015 Mar 12.

Authors

Sergey M Ivanov¹, Alexey A Lagunin², Pavel V Pogodin², Dmitry A Filimonov³, Vladimir V Poroikov²

Affiliations

¹ *Institute of Biomedical Chemistry, 119121 Moscow, Russia and Medico-Biological Faculty, Pirogov Russian National Research Medical University, 117997 Moscow, Russia sergey.ivanov@ibmc.msk.ru.
² *Institute of Biomedical Chemistry, 119121 Moscow, Russia and Medico-Biological Faculty, Pirogov Russian National Research Medical University, 117997 Moscow, Russia *Institute of Biomedical Chemistry, 119121 Moscow, Russia and Medico-Biological Faculty, Pirogov Russian National Research Medical University, 117997 Moscow, Russia.
³ *Institute of Biomedical Chemistry, 119121 Moscow, Russia and Medico-Biological Faculty, Pirogov Russian National Research Medical University, 117997 Moscow, Russia.

PMID: 25766883
DOI: 10.1093/toxsci/kfv054

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 behavior of the CRN caused by the inhibition of each node for the identification of potential VT-related targets. As a result, we revealed 312 potential VT-related targets and classified them into 3 confidence categories: high (36 proteins), medium (111 proteins), and low (165 proteins) classes. The most probable targets may serve as a basis for experimental confirmation and may be used for in vitro or in silico assessments of the relationships between drug candidates and drug-induced VT, the understanding of contraindications of drug application and dangerous drug combinations.

Keywords: cardiomyocyte; drug-target interaction profile; off-target; signal transduction network; torsades de pointes; ventricular tachycardia.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Action Potentials / drug effects
Algorithms
Computer Simulation
Databases, Pharmaceutical
Heart Conduction System / drug effects*
Heart Conduction System / metabolism
Heart Conduction System / physiopathology
Heart Rate / drug effects
Humans
Long QT Syndrome / chemically induced*
Long QT Syndrome / metabolism
Long QT Syndrome / physiopathology
Molecular Structure
Myocytes, Cardiac / drug effects*
Myocytes, Cardiac / metabolism
Protein Interaction Maps
Risk Assessment
Signal Transduction / drug effects*
Structure-Activity Relationship
Systems Biology*
Tachycardia, Ventricular / chemically induced*
Tachycardia, Ventricular / metabolism
Tachycardia, Ventricular / physiopathology
Toxicity Tests / methods*