Stereoselective block of hERG channel by bupivacaine scrutinized at molecular level

Area of Science:

• Cardiovascular pharmacology
• Molecular biophysics
• Computational chemistry

Background:

• The hERG channel is vital for cardiac action potential duration.
• hERG channel block can lead to dangerous arrhythmias like torsades de pointes.
• Stereoselectivity in hERG channel block is not well understood.

Purpose of the Study:

• To investigate the molecular basis of bupivacaine's stereoselective block of the hERG channel.
• To understand the principles underlying differential enantiomer binding to hERG.
• To establish a structural guideline for in silico screening of cardiotoxic drug candidates.

Main Methods:

• Molecular modeling techniques, including docking simulations.
• Prediction of putative binding modes for levo-(S)- and dextro-(R)-bupivacaine.
• Analysis of ligand-protein interactions within an open hERG channel model.

Main Results:

• Docking simulations predicted distinct binding modes for bupivacaine enantiomers.
• Estimated binding energies correlated with experimental electrophysiology data.
• Confirmed stereoselective binding of bupivacaine to the hERG channel at the molecular level.

Conclusions:

• Molecular modeling provides insights into the stereoselective interaction between bupivacaine and the hERG channel.
• The findings support experimental observations of differential enantiomer affinity.
• This study provides a foundation for in silico filtering of potentially cardiotoxic compounds.