Key result
Screening of 70 ion channel ligands in a zebrafish model identified six compounds with strong in vivo cardiotoxicity, five of which may interact with the L-type calcium channel.
Why the study?
Cardiotoxicity is one of the most common reasons for drug retraction, and zebrafish models can screen drug libraries for potential cardiotoxicity in a high-throughput manner while adhering to 3R principles.
A combined in vivo zebrafish and in silico molecular docking approach successfully screened ion channel ligands for cardiotoxicity, identifying potential arrhythmogenic compounds.
May flag cardiotoxicity risks in candidates; animal data leaves open human translation.
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.
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Sampurna et al. (2019) studied Cardiotoxicity. Ion channel ligands was evaluated on Cardiotoxicity in vivo and molecular docking interactions. Screening of 70 ion channel ligands in a zebrafish model identified six compounds with strong in vivo cardiotoxicity, five of which may interact with the L-type calcium channel.
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