Abstract:

Background and research questions
Voltage-gated ion channel proteins, such as KV11.1 and CaV1.2, are critical in maintaining regular cardiac rhythm. The hERG potassium channel, KV11.1, is responsible for cardiac repolarization, and its inhibition by drug molecules may lead to prolonged QT intervals and arrhythmias. Additionally, CaV1.2 is the main Ca2+ channel expressed in cardiac muscle cells, and its drug interactions can also alter heart rhythms. Since drug-ion channel interactions may pose serious clinical concerns, this study aims to investigate drug-binding affinities with cardiac ion channels using in-silico molecular docking models and to provide accurate arrhythmia risk predictions.

Methods
In this study, approximately 60 drugs were selected based on their known cardiac risks. The small molecules were sourced from PubChem and prepared with the dominant protonation states at the physiological pH. Molecular docking was performed using Schrödinger Glide and OpenEye FRED software; we also employed various programs such as PyMol, VMD, and ChimeraX, for structural analysis. Computed drug binding affinities were further used in logistic regression models to assess arrhythmia risks.

Results
The study demonstrated reasonable correlation between binding scores and experimental IC50 values although variation was observed depending on the protein structure and conformational state. Binding poses aligned well with the available cryo-EM structures. Logistic regression models achieved up to 77% accuracy in classifying high and low Torsades de pointes (TdP) arrhythmia risks implying their potential clinical applications.

Conclusions
This molecular docking study has provided a fairly accurate description of ion channel protein – ligand interactions, contributing to our understanding of drug-induced cardiac risks and aiding in drug safety screening. To improve the prediction accuracy, future work can incorporate additional docking platforms and molecular dynamic simulation approaches.

Speaker:

Ensley Jang, University of California, Davis

Ensley is an undergraduate student majoring in Pharmaceutical Chemistry at University of California, Davis. Her interests lie in molecular mechanisms underlying disease and drug interactions.