title: 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 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.
authors.affiliation: *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.
authors.forename: Sergey M
authors.initials: SM
authors.lastname: Ivanov
authors.affiliation: *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.
authors.forename: Alexey A
authors.initials: AA
authors.lastname: Lagunin
authors.affiliation: *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.
authors.forename: Pavel V
authors.initials: PV
authors.lastname: Pogodin
authors.affiliation: *Institute of Biomedical Chemistry, 119121 Moscow, Russia and Medico-Biological Faculty, Pirogov Russian National Research Medical University, 117997 Moscow, Russia.
authors.forename: Dmitry A
authors.initials: DA
authors.lastname: Filimonov
authors.affiliation: *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.
authors.forename: Vladimir V
authors.initials: VV
authors.lastname: Poroikov
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000465:Algorithms; D003198:Computer Simulation; D062313:Databases, Pharmaceutical; D006329:Heart Conduction System / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D015394:Molecular Structure; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D060066:Protein Interaction Maps; D018570:Risk Assessment; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship; D049490:Systems Biology; D017180:Tachycardia, Ventricular / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D018675:Toxicity Tests / Q000379:methods*
keywords: cardiomyocyte; drug-target interaction profile; off-target; signal transduction network; torsades de pointes; ventricular tachycardia