Study Yields Clues to Molecular Functions of Sodium Channel Blocking Drugs

Amanda Buyan, PhD

Researchers at Australia National University have uncovered new molecular properties of common sodium-blocking drugs—information they hope will lead to the design of more specific drugs with fewer adverse effects to treat disorders like pain and epilepsy.

The investigative team took advantage of the super computing power available at the university to compare the binding properties of 9 different drugs known to act on sodium channels.

“Though there are previous simulation studies that have looked at these types of medications, this is one of—if not the first—to look at this large of a range of medications,” Amanda Buyan, PhD, a postdoctoral fellow at ANU and the lead author of the study, told MD Magazine.

Sodium channels are found throughout the brain and body and are crucial to normal brain function, and their blockers are used to treat a variety of disorders ranging from neuropathic pain to heart arrhythmias. Although some of these drugs were developed decades ago, scientists know very little about how they work at a molecular level. Since they tend to act on many different sodium channels throughout the body, they can also cause myriad unpleasant adverse effects, such as dry mouth, blurred vision, constipation, diarrhea, and more in certain at-risk patients.

The body has 2 main types of sodium channels—voltage gated and ligand-gated. Within those are several more subtypes based on the structures and organization of the proteins that make them up. The researchers focused on 2 different voltage-gated sodium channels: NavMs, a bacterial sodium channel and NavPas, a eukaryotic sodium channel.

Buyan and the researchers used replica exchange solute tempering (REST) to generate computer simulations in order to investigate the binding preferences of the 9 different drugs known to act on these receptors.

In addition to observing the drugs binding to a well-known site found on helix 6 of the receptor, they also identified a second binding site that attracts only the positively-charged portion of the drugs. The experiments also showed that neutral compounds, rather than charged compounds, crossed the channel’s bilayer more easily.

The team hopes that these findings will be a first step in helping researchers design drugs that are better able to target specific receptors to exert therapeutic effects.

“The medications used for local anesthetics and epilepsy affect the same targets, and to reduce [adverse] effects, we will have to do more research in either modifying existing drugs to be more specific or attempt to treat the same targets in a different manner,” Buyan said. From there, she noted, they will need to decide how to proceed with different strategies.

“[The question is] do we look at a different place on the target? Do we modify existing drugs?” Buyan added.

The study, “Protonation state of inhibitors determines interaction sites within voltage-gated sodium channels,” was published in Proceedings of the National Academy of Sciences of the United States of America.