High fidelity computational approaches to exploit new structures of cardiac ion channels

Why did we fund this project?

This award aims to develop a computational approach to predict whether a compound will impact cardiac ion channel function, replacing the use of some animals in the drug development process.

Cardiac ion channels play an essential role in coordinating the synchronous contraction across the heart. Any compound that impacts a cardiac ion channel has the potential to disrupt this process causing arrhythmias or other cardiotoxic effects. Cardiotoxicity assessment is carried out at various stages during drug development initially in in vitro or ex vivo assays using human induced pluripotent stem cells or using heart tissue and cells from small animals such as guinea pigs, rabbits, or rats. Later in development, cardiovascular safety including electrophysiology, mechanical read-outs of cardiac function and pathophysiology are assessed as part of a core battery of regulatory pharmacology and toxicology tests usually performed in dogs or non-human primates. In silico methods are used early in drug development to investigate potential cardiac liabilities for specific ion channels. Dr Andrew Leach has previously studied the hERG ion channel and more recently has developed a computational method to determine the strength of interactions between a compound and any protein. This new method will be applied to understand the effect of any compound on each of the ion channels that will be studied, in particular whether the channel would potentially be blocked or maintained in an open state.

The student will develop new computational models, using Andrew’s method, with recently published data describing the molecular structure of relevant cardiac ion channels. These models will be validated by running calculations of molecules with known affinities to the ion channel being modelled. To further demonstrate the utility of the model, the student will also use the calculations to design compounds to target specific ion channels, such as the Ryanodine receptor a common cause of arrhythmias in patients. The student will develop skills in mathematical modelling, compound design and computational chemistry.

Before a new drug can be tested in humans, it is required to undergo testing in animals. A key part of this is to check that the medicine does not cause disruptions or changes to the heart’s regular rhythm. This is usually tested by giving the compound to dogs and at least one other species of animal, even including primates, with monitoring equipment surgically implanted. Other tests require surgical opening of the chest to work on a living heart while others use hearts from sacrificed animals.These tests are performed after years of drug discovery has taken place. Along the way thousands of alternative compounds will have been considered and rejected. If these animal tests show the selected compound interferes with the heart’s rhythm, it is often too late to change and go back to one of the alternative compounds. To avoid this, drug companies trying to find new medicines do lots of animal testing early in the process. We want to provide an alternative to these tests that takes place entirely inside a computer. If it works, it will be even better than the animal tests because it will tell researchers how to solve any problem. The student who develops this new test will show that it works by applying it in our ongoing BHF supported project to discover a new medicine to prevent arrythmias.

The heart’s beat involves many so-called ion channels. These are like tiny wires that allow currents to flow and make the heart muscle pump. Molecules can disrupt these currents by sticking in the ion channel like a bottle stopper or wedging them open. If we know the structure of the channel and we have a good way to predict how well a molecule might fit into them, we can predict the effect that a compound might have without even having to make it. Given that it is much easier to propose testing on animals once a compound has been made, this new approach has a powerful possibility to change the mindset away from using animal testing to build the necessary confidence to proceed through drug discovery.

The molecular structure of the most relevant ion channels has been recently (2020 and 2021) much better understood thanks to a new technique that won the Nobel prize for chemistry in 2017 and Dr Leach has developed a new way to calculate the strength of interaction between molecules and we propose combining this new method with the new structures to create our alternative to animal tests. The student will create and test models for several of the ion channels in the first two years of their project.

Application of the models will be made in our project to discover compounds that block one of the ion channels that causes arrythmias when it gets too leaky; the so-called Ryanodine receptor. We believe that if we can find the right compound to block the Ryanodine receptor, it will have the potential to help many of the almost 1 million people who are living with heart failure in the UK and therefore at increased risk of suffering the consequences of arrythmia. We will apply the computational method that we develop to help us design the best compound and in doing so we will road test the method and learn how to improve it. This should lead to a virtuous circle where we continually improve our calculations and get better compounds.

The student would be joining a vibrant research environment that would allow them to work closely with computational and synthetic chemists as well as biologists and clinicians. In the first phase of their work they will be based in a computational research lab but the project has latitude for them to tailor the later stages to their interests and aspirations and they could work in a chemical laboratory making compounds or with biologists to understand how the compounds have their effect.