PRACE is joining the battle against COVID-19 by providing huge computational power – 195 000 000 core hours – to the first ten projects awarded under the Fast Track Call for Proposals to support the mitigation of the impact of the pandemic. And this is only the beginning.
There are currently no registered therapies for treating coronavirus infections. Because of the time-consuming process of new drug development, drug repositioning may be the only solution to the epidemic of sudden infectious diseases.
The PRACE Fast Track Call for Proposals aims to speed up the process to find treatments
The studies awarded by PRACE independently analysed a number of proteins encoded by SARS-CoV-2 genes, compared them with proteins from other coronaviruses, predicted their structures and built 19 structures that could analysed via homology modelling. By performing target-based virtual ligand screening, a total of 21 targets (including two human targets) were screened against compound libraries, including ZINC drug database and a database of natural products.
Some of the projects made the structure and screening results of important targets such as 3-chymotrypsin-like protease (3CLpro), Spike, RNA-dependent RNA polymerase (RdRp), and papain like protease (PLpro) visible. In addition, a database of 78 commonly used anti-viral drugs, including those currently on the market and undergoing clinical trials for SARS-CoV-2, was constructed. Possible targets of these compounds and potential drugs acting on a certain target were predicted.
These projects will provide new lead compounds and targets for further in vitro and in vivo studies of SARS-CoV-2 (virus strain causing coronavirus disease COVID-19), new insights for those drugs currently undergoing clinical studies and also possible new strategies for drug repositioning to treat SARS-CoV-2 infections.
All this is possible thanks to one of the most powerful tools for finding possible medicines and inhibitors: virtual ligand screening and virtual drug design. Both techniques directly use supercomputer simulations, extreme-scale supercomputing simulations, that can only be performed on supercomputers with tens of thousands of cores. PRACE provides just such supercomputers to the research community.
With these powerful machines, the first 10 “HPCvsVirus” projects will be realised. Below you can read a summary of the work each project will undertake.
COVID-HP is led by Prof. Jean-Philip Piquemal from Sorbonne University in France together with complementary teams from leading universities and institutes in France and the USA. In the coming six months scientists will conduct biomolecular research to understand the mechanisms of the virus infection and bio-simulations to develop therapeutics.
The consortium has prepared different traps for the virus: they aim to find inhibitors capable of selectively targeting some of the key proteins, as well as key nucleic acid sequences in its genome.
All these complex studies and simulations require high computational power and PRACE awarded the consortium 20 000 000 core hours on Joliot-Curie Rome, hosted by GENCI at CEA, France.
Characterisation of a peptide network with a combined anti-viral and anti-inflammatory activity against COVID-19 is led by Dr Hansel Gómez Martínez from NURITAS in Ireland. The project team will look for bioactive peptides that can bind to as many targets as possible in SARS-CoV-2. The company has identified six targets from the virus – spike protein, main protease, nucleocapsid protein, NSP3, NSP10, and NSP15, and will extend that list through modelling. The authors will use purification mass spectrometry to identify 332 high confidence SARS-CoV-2-human protein-protein interactions, including 66 druggable human proteins which are targets for drugs.
The expected outcome is a cocktail of natural peptides, unlocked from natural sources and exhibiting anti-viral properties against COVID-19. Moreover, since similar coronaviruses use comparable infection mechanisms, these peptides could, in principle, provide some universal protection against other viruses of the same family.
For all this the team of Dr Hansel Gómez Martínez from NURITAS needed access to an HPC facility for at least six months and the project was awarded by PRACE with 40 000 000 core hours on Piz Daint, hosted by CSCS, Switzerland.
COVID19: Computational screening and improvement of viral protein inhibitors. It is led by Prof. Dr Gerrit Groenhof from the University of Jyväskylä in Finland and his multidisciplinary team. The main purpose of the project is to analyse the S-protein of SARS-CoV-2. The scientists are specialists in synthetic chemistry, molecular modelling, infectious diseases and other disciplines. They have two anti-viral strategies: inhibiting or blocking of the viral spike protein that recognises the ACE2 receptor on the human cell, with aptamers. And second targeting the viral RNA-dependent RNA polymerase (RdRp) and possibly attacking it with chemically modified nucleotide analogues, such as remdesivir.
With molecular dynamics simulations and free energy computations, the scientists will predict the effects of chemical modification of nucleotide bases and investigate possible cooperative effects of inhibitors. If the process is successful, the consortium will anticipate novel post-infection therapeutics to help slow down the COVID-19 outbreak until a suitable vaccine is available. The idea is to make this drug design and protocols available for possible future infections. PRACE awarded the project with 15 000 000 core hours on Joliot-Curie Rome hosted by GENCI at CEA, France.
Characterization of SARS-CoV-2 envelope small membrane protein (E) is led by Prof. Matteo Dal Peraro from École Polytechnique at Lausanne in Switzerland. It is related to one of the most interesting and unknown proteins in the virus. Small membrane protein – E is a short name of it – with 75 amino acids is key for viral assembly and intracellular trafficking of virions.
For that reason, E is the main focus of Prof. Matteo Dal Peraro. He and his team will perform atomistic molecular dynamics simulations to characterise this protein in its specific membrane environments and its properties as an ion channel.
The concrete output of this simulation will be the definition of CoV2 E in physiological states relevant for the viral life cycle. Once made available to the community, this dataset can be the foundation for structure-based drug development as well as for drug repurposing campaigns to discover anti-virals. Moreover, these models will help scientists to explore and rationalise the molecular mechanisms of the viral infection, implicated with CoV2 E.
To perform these atomistic molecular dynamics (MD) simulations in parallel, PRACE awarded the team of Prof. Matteo Dal Peraro 10 000 000 core hours on Piz Daint hosted by CSCS, Switzerland.
Polypharmacology-based anti-viral design led by Dr Daniel Soler from Nostrum Biodiscovery in Spain, and his team. They devised an approach for addressing compounds with activity among several strains of SARS-CoV-2, SARS, and MERS. These strains will be targets of a promising hit molecule that the team expects to obtain with virtual screening and experimental assays.
The scientists need high computational power and algorithms to sample a considerable number of compounds by performing virtual screens of hundreds of millions of molecules. A hierarchical approach that integrates virtual screening of vast libraries together with state-of-the-art induced-fit techniques will allow to filter the most promising compounds within a reasonable amount of time.
To perform these complicated calculations and simulations, PRACE awarded the project of Nostrum Biodiscovery with 4 000 000 core hours on SuperMUC-NG, hosted by GCS at LRZ, Germany.
Drug design on the 3CL-pro (Mpro) target protein of SARS-CoV2 using fast switching massively parallel alchemical approaches for absolute binding free energy determination is led by Prof. Piero Procacci from the University of Florence in Italy and revolves around virtual design of inhibitors against replication of the coronavirus. Inhibitors are small molecule compounds: the weapons of the team to attack the 3CL-pro main protease of the SARS-CoV2.
On an HPC system, NS-approach can afford an in-silico measure of any given small molecule compound for 3CL-pro. The project will use available libraries of putative 3CL-pro inhibitors to identify a non-toxic, orally administrable, commercially available or of facile synthesis 3CL-pro inhibitor to timely proceed to the in vitro and in vivo assays.
For this innovative drug design, PRACE awarded the project the necessary 20 000 000 core hours on Marconi100, hosted by CINECA, Italy.
Molecular Dynamics investigation of the interaction between ACE2 and the spike glycoprotein of SARS-CoV-2, in comparison with its predecessors from bat and pangolin takes a completely different approach. It is led by Prof. Giovanni Chillemi from University of Tuscia and CNR in Italy. He and his team plan a time-travel molecular dynamics investigation: interaction between a receptor of human cells – ACE2 and the spike glycoprotein of SARS-CoV-2 – and its predecessors in bats and pangolins.
The goal of this project is to compare structural and dynamic properties of the spike glycoprotein in SARS-CoV-2, bat-SL-CoVs, BetaCoV_pangolin and the Italian variant hCoV-19/INMI1-isl/2020 by means of micro-second molecular dynamic simulations. The idea is to shed light on some specific features the virus gained that have facilitated its successful spread as compared to its predecessors. These results are preparatory for the identification of inhibitors that may reduce substantially the infectiousness of SARS-CoV-2.
High computational power is necessary for such research: only spike glycoprotein trimer already has 600 000 atoms, ACE2 in complex with one spike trimer has 1.2 million atoms and with two 2.1 million atoms. PRACE awarded the team with 3 000 000 core hours on Marconi100, hosted by CINECA, Italy.
CardioVascular-COVID is a project led by Dr Jazmin Aguado-Sierra from Barcelona Supercomputing Center that will shed light on the effect of anti-malarial drugs on cardiovascular systems – people with various heart diseases with different comorbidities are among the most affected by COVID-19. Researchers of Barcelona Supercomputing Center (BSC) will also study anti-malarial and antibiotic cardiotoxicity – two main problems that require quick generation of evidence and information towards their use by clinicians. The purpose of the project is to help to improve treatment of cardiac patients, affected most severely by the disease and ultimately reducing mortality.
The above is the first goal of the project, the second is to explore Venous-Arterial Extracorporeal membrane oxygenation therapy and the North-South Syndrome on patients with profound respiratory failure. For many of them, infection with COVID-19 results in dangerous respiratory failure, requiring ventilatory support in the intensive care unit.
All this requires a multidisciplinary team and for the project BSC will collaborate with the Visible Heart Laboratory, and the University of Minnesota Medical Centre. PRACE awarded 7 800 000 core hours on Joliot-Curie Rome, hosted by GENCI at CEA, France.
Targeting the interface of the COVID-19 spike protein with the ACE2 receptor is led by Prof. Francesco Luigi Gervasio from University College in London and it has a different approach. PRACE awarded it for the design of peptide-based binders that will block interactions between a spike (S) of the virus and a human cell receptor (ACE2), which acts as the door for the virus to enter the cell. Just this interface is the target of Prof. Francesco Luigi Gervasio and his team coming from several scientific groups. Disrupting the SARS-CoV-2 spike binding to ACE2 with rationally designed drugs has the potential to inhibit the virus from entering human cells. In particular, peptide-based binders are an attractive solution to stop dangerous interaction.
The team of Gervasio, UCL computational and experimental groups in collaboration with the Mount Sinai school of medicine and a company at the forefront of machine learning (ML), propose to design peptides and peptide-polymer conjugates, targeting the spike S-ACE2 interface.
The simulations and the results can be used to synthesise the nanocarriers for anti-viral therapy, which will be tested at UCL and Mount Sinai.
To this end PRACE awarded the project 30 000 000 core hours on Hawk, hosted by GCS at HLRS, Germany.
Targeting conformational changes implicated in early events of viral entry is a project devising another trap to catch the virus. The project is that of Prof. Francisco Javier Luque from the University of Barcelona in Spain. It has two ambitious goals. First, to disrupt viral entry by finding small molecules able to interfere with the conformational changes in the spike protein, prior to binding to the host cell. Second to characterise the structural and energetic changes, implicated in transition in both free and ligand-bound spike proteins.
The team of Prof. Luque has a precise model of this collaboration between a spike and human cell receptor and found a specific inactive state. The scientists would like to find a small compound that might stabilise it. They will attempt this through binding to a pocket located at the hinge region, which defines a putative druggable cavity. This was estimated from two independent druggability predictors.
These stabilisers are hiding the determinants of ACE2 binding and the disclosure of a moderate stabiliser could be a promising finding.
PRACE awarded the project 15 300 000 core hours on Hawk, hosted by GCS at HLRS, Germany.