PUBLICATION

Cardiac Rhythm and Molecular Docking Studies of Ion Channel Ligands with Cardiotoxicity in Zebrafish

Authors
Sampurna, B.P., Santoso, F., Lee, J.H., Yu, W.H., Wu, C.C., Audira, G., Juniardi, S., Chen, J.R., Lin, Y.T., Hsiao, C.D.
ID
ZDB-PUB-190613-1
Date
2019
Source
Cells   8(6): (Journal)
Registered Authors
Hsiao, Chung-Der
Keywords
cardiotoxicity, heart, ion channel ligand, molecular docking, zebrafish
MeSH Terms
  • Animals
  • Binding Sites
  • Calcium Channels, L-Type/chemistry
  • Calcium Channels, L-Type/metabolism
  • Embryo, Nonmammalian/metabolism
  • Heart Rate*/drug effects
  • Hydrogen Bonding
  • Ion Channels/chemistry
  • Ion Channels/metabolism*
  • Ligands*
  • Molecular Docking Simulation
  • Protein Structure, Tertiary
  • Small Molecule Libraries/chemistry
  • Small Molecule Libraries/metabolism
  • Small Molecule Libraries/pharmacology
  • Zebrafish/growth & development
  • Zebrafish/metabolism*
  • Zebrafish Proteins/chemistry
  • Zebrafish Proteins/metabolism*
PubMed
31185584 Full text @ Cells
Abstract
Safety is one of the most important and critical issues in drug development. Many drugs were abandoned in clinical trials and retracted from the market because of unknown side effects. Cardiotoxicity is one of the most common reasons for drug retraction due to its potential side effects, i.e., inducing either tachycardia, bradycardia or arrhythmia. The zebrafish model could be used to screen drug libraries with potential cardiotoxicity in a high-throughput manner. In addition, the fundamental principles of replacement, reduction, and refinement of laboratory animal usage, 3R, could be achieved by using zebrafish as an alternative to animal models. In this study, we used a simple ImageJ-based method to evaluate and screen 70 ion channel ligands and successfully identify six compounds with strong cardiotoxicity in vivo. Next, we conducted an in silico-based molecular docking simulation to elucidate five identified compounds that might interact with domain III or domain IV of the Danio rerio L-type calcium channel (LTCC), a known pharmaceutically important target for arrhythmia. In conclusion, in this study, we provide a web lab and dry lab combinatorial approach to perform in vivo cardiotoxicity drug screening and in silico mechanistic studies.
Genes / Markers
Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping