New simulations provide insights into important interactions between drugs and heart cells at the atomic level

New simulations provide insights into important interactions between drugs and heart cells at the atomic level

To unravel the mysterious mechanisms of drug effectiveness to treat cardiac arrhythmias, a group of researchers at UC Davis have developed novel simulations that provide insights into key interactions between drugs and heart cells at the atomic level.

These simulations were published today inPNAS(Proceedings of the National Academy of Sciences) could point the way to better development of new antiarrhythmic drugs that target voltage-gated sodium channels (NaV), specialized protein molecules in the heart cell membrane.

Sodium channels act as gatekeepers that regulate the electrical activity of heart cells. When the electrical signals that coordinate heartbeats do not function properly, heartbeats may become irregular and are considered to be in an arrhythmic state.

A class of antiarrhythmic drugs acts on NaV channels to influence the electrical activity and beating of the heart. However, the long-standing failures in drug treatment of cardiac arrhythmias are mainly due to the inability to predict the effects of developed drugs on the activity of NaV and other cardiac ion channels.

“Prior to our study, there was no effective preclinical methodology to distinguish useful or potentially harmful drugs at the molecular level,” said Vladimir Yarov-Yarovoy, associate professor in the Department of Physiology and Membrane Biology at UC Davis.

“To develop and test novel drugs to treat cardiovascular diseases and minimize their side effects, the mechanism of antiarrhythmic drug interactions with NaV channels needs to be understood at the atomic level,” he said.

Thanks to several technological breakthroughs and an increasing number of available high-resolution structures of ion channels such as NaV, researchers are now able to simulate these structures and modulate cardiac cell activity by studying their interactions at atomic resolution. Using computer modeling software Rosetta, the researchers were able to create a model of the human NaV channel based on the very similar structure of the electric eel's NaV channel.

NaV channels open to allow sodium ions to flow into heart cells and close within milliseconds. When the drug molecules enter these channels, they bind tightly to the receptor site within the protein, preventing the sodium ions from entering the cell and blocking the channel conduction. This change in conduction affects the electrical activity and beat of the heart.

In the developed atom model simulations, two drug molecules are observed to enter the central pore of the channel and bind to the receptor site of the protein, creating the “hot spots,” areas where the most favorable drug-protein interactions occur. This binding activity triggers a so-called high-affinity state of the channel.

"The high affinity state of the channel is considered the most important state for studying the binding mechanism between drugs and proteins. Now and for the first time, we can understand how this binding process occurs at the atomic level," Yarov-Yarovoy added.

Multi-microsecond simulations of the interaction of lidocaine (antiarrhythmic and local anesthetic) with sodium channels revealed a channel pore access route through the intracellular gate and a novel access route through a relatively small lateral opening known as a fenestration.

Combining molecular modeling software with simulations to study interactions between drug channels is a novel approach that will enable automated virtual drug screening in the future. This technology can be applied to any ion channel and would be beneficial for multiple treatments. Ultimately, this approach advances precision medicine by predicting individual patient responses to drug therapy based on the patient's specific ion channel mutation.

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