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How do drugs bind to cardiac potassium channels?

Victor Chang Cardiac Research Institute & University of New South Wales

  • Cardiovascular Senior Researcher Grant
Date Funded:
  • 1 February, 2022
Chief Investigator/s:
  • Professor Jamie Ian Vandenberg

Project Summary

To determine how drugs bind to hERG channels and then develop a computer program to predict drug modifications to reduce affinity for hERG channels.

The main researcher for this project is Professor Jamie Ian Vandenberg.

What is the issue for NSW?

Before any new drug can come to market it must pass stringent pre-clinical testing to ensure it is safe. One of the most commonly encountered off-target effects is block of an ion channel protein expressed in the heart, called the hERG potassium channel.  Inadvertent drug block of HERG potassium channels can affect all drug classes and all people so it is a universal problem rather than NSW specific. Our development of a more rational approach to help design out hERG drug block will facilitate development of new drugs for everyone.

More generally, drugs that bind to membrane proteins represent more than 50% of currently prescribed drugs and is a burgeoning area of drug development. Studies of the structural basis of membrane protein function, however, is an area where NSW is under-represented compared to Victoria and Queensland. This project will help to remedy this shortcoming. There is also the potential to develop intellectual property that could bring economic benefits to NSW.

What does the research aim to do and how?

We will use super high resolution electron microscopy to determine high resolution structures of HERG channels in both drug-bound and drug-free states. This information will be used to constrain computer models that can predict how drugs bind to hERG channels and how we can modify drugs to minimise their binding to the channels. This computer model should enable a more evidence-based approach to improving drug discovery pipelines that ensure safer drugs in the future.