Using molecular dynamics to find drugs and vaccines for COVID-19

Overview of drug design process

Molecular dynamics simulations allow us to see into the hidden atomic-scale world that makes up everything we see. Understanding SARS-CoV-2 at this level is helping Vangelis Daskalakis of the Cyprus University of Technology to identify weaknesses in the virus that can be exploited and targeted through drugs and vaccines.

The COVID-19 pandemic has created a high demand for the characterisation of molecules that can inhibit viral functions, as well as for the production of vaccines that can trigger an efficient and safe immune system response. The rapidly spreading virus has sparked an unprecedented response from the research community as the world faces a health challenge of enormous proportions.

Vangelis Daskalakis of the Cyprus University of Technology is a researcher who uses molecular dynamics simulations to study how molecules within biological systems move and interact. These types of simulations can show the role that dynamics play in the function of biological molecules.

Vangelis Daskalakis of Cyprus University of Technology

Vangelis Daskalakis

Collaborating with colleagues from the University of Crete (School of Medicine, Dept. of Biology), Daskalakis and his team decided to use their skills in the fight against the pandemic. They believe that research on SARS-CoV-2 should focus on proteins that exhibit higher evolutionary conservation and lower mutation rates, and that are potential drug targets or sources of epitopes. Epitopes – small parts of antigens that are recognised by the immune system – could potentially be used to develop vaccines that offer protection against Covid-19.

In SARS-CoV-2, both the main protease and the nucleocapsid protein exhibit such characteristics, and are therefore ideal targets for the simulations. In addition, there is no human homologue of the main protease, which makes it an ideal antiviral target as it will not interfere with other human cellular functions. Daskalakis says that any strategy against the disease should include several proteins instead of a single one, as there is a high risk of drug resistance induced by rapid evolution in the viral genetic material. As such, the team has been looking at these two protein targets on the SARS-CoV-2 virus as part of a PRACE project. The main protease is a non-structural protein that cleaves the viral polyprotein into functional proteins – a critical step during viral replication. The second target, the nucleocapsid, is used in the packaging of the viral genome through protein oligomerisation and in keeping it stable inside the virus.

Using 3D structures of these proteins obtained from Cryogenic Electron Microscopy and X-ray crystallography as a starting point, Daskalakis and his team have employed enhanced sampling methods to try and ascertain the shape that these molecules take in vivo. After that, they screened a large database of natural products against these proteins to see if they could find any potential inhibitors to their functions. These fundamental studies required enormous computational power and PRACE awarded the project with 16 million core hours on Joliot-Curie Rome, hosted by GENCI at CEA, France. So far, the team has used those 16 million core hours and has been granted an extension of another 2 million core hours to continue the work.

Overview of drug design process

The viral proteins can become efficient targets of drug-design via computer simulations. The virus capsid includes the spike (S), the envelope (E), the membrane (M), and the nucleocapsid proteins (N) for packaging the viral genome. The viral RNA is translated into a polyprotein. The virial main protease (MPro), like scissors, cleaves the viral polyprotein to functional proteins; a critical step during viral replication and production. Computer simulations translate the protein structures into digits to be ready for production simulations.

“In essence, what we do is we create digital versions of these two proteins – the main protease and the nucleocapsid – and use them to carry out molecular dynamics simulations,” explains Daskalakis. “We employ a method called replica exchange to predict the actual conformations of the proteins. These conformations are then tested against a large database of natural products to see if any of them might inhibit their function. At this point, we have identified two natural products that may be able to facilitate the weakening of the main protease function, as well as weaken the nucleocapsid interaction with other proteins, called importins, essential for importing the viral RNA into the host cell nucleus.

“For instance, the main protease is only active when it is in the form of a dimer, in which two molecules are bonded together,” continues Daskalakis. “Any natural product that can destabilise this dimerisation has the potential to be a potent drug against the virus. So far, we have identified one such product, called Fortunellin, a natural product found in the fruits of Citrus japonica var. margarita (kumquat). As for the nucleocapsid-importin interactions, these are weakened by p-cymene, a constituent in the essential oils of more than 100 plant species such as the oil of Thymus vulgaris and Origanum vulgare subsp glandulosum. These findings are currently under peer review for publication.”

Based on the observed dynamics – the motion of the atoms in the molecules through time – the team has also been able to identify a number of special domains of the proteins that are important to their function. They then cross-referenced these domains against a database of epitope fragments to see if they might be useful targets for potential epitope-based vaccines.

Applied production simulation method

1. The production simulation includes a method in which protein replicas are heated to temperatures between 37-127oC, the replicas are allowed to exchange, in order to facilitate efficient conformational sampling even at lower temperatures. 2. These exchanges are happening in the presence and the absence of natural products (protein inhibitors) that may lead to destabilized (inactive) variants of the proteins. 3. Essential protein motions identify important protein domains for the virial function that can be used as epitopes for vaccination and trigger an immune response.

Daskalakis believes that the huge response of the scientific community towards the pandemic is the right approach if the world is to see results in a timely manner. “First line research has been accelerated beyond anything we have ever seen before, and this is likely to produce some errors which might hinder instead of speed up the fight against the pandemic,” he says. “However, among the thousands of research projects there will be a few that can certainly make an impact and accelerate the recovery from the pandemic.

“My opinion is that we need to be more careful than normal in critically evaluating everything that is published. However, we cannot afford to lose important results that can potentially make a difference. It is like throwing dice. Only when we increase the number of throws will we get the number of possibilities we need – even though many will be dead-ends – especially when research in this field is in its infancy.”

Looking to the future, Daskalakis is collaborating with experts from the University of Crete in experimental endocrinology, virology and in the natural products being examined. “These collaborations will help us to see whether or not the products we are looking at might potentially interfere with other normal metabolic pathways, and also help us to work out how we might go about sourcing these products for clinical use. We firmly believe that trying to find natural products that have already been licensed is the way forward in terms of fighting the pandemic. At this point, we do not have the time to develop a medicine from scratch and ensure that it is safe.”

This article was also published in PRACE Digest 2020.

More information:

Resources awarded:
16 million core hours on Joliot-Curie Rome, hosted by GENCI at CEA, France


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