Published 16 June 2020
The EU’s war against COVID-19 continues and PRACE awarded another ten projects with a total of 227 578 000 core hours under the Fast Track Call for Proposals to support the mitigation of the impact of the pandemic.
With the accumulation of knowledge about this novel coronavirus, scientists are discovering new possibilities and tools to exploit its weaknesses and PRACE offers the most powerful supercomputers for their breakthroughs.
The main goal of these studies is to find ways to block the coronavirus and stop its replication in human cells, how to create more intelligent therapies, drug repositioning, anti-viral drugs, and of course, vaccines. And also, how to improve tests, how to make them more accurate, how to obtain novel and better SARS-CoV-2 therapeutics and diagnostics based on antibodies.
Moreover, the scientists will use world-class computational power to create simulations to find adequate levels of oxygen and carbon dioxide for each patient according to their condition and comorbidities. Setting these levels correctly is currently one of the main problems in treatment.
One of the PRACE-awarded studies will pinpoint the weaknesses of the lysosomal-endosomal TPC2 ion channels. This system in our cells is involved in different diseases, such as cancer, Parkinson, and viral infections. Now for the first time, it will be studied in more detail and possibly achieve important breakthroughs.
Several projects make the structure and screening results of targets in the virus such as 3CLpro, Spike, nsp1, RNA-dependent RNA polymerase, etc. visible, clarify their functions, and how they can be blocked with various compounds and tools.
To find all these answers and to make new discoveries scientists need to use different libraries with tens of millions of compounds, including ZINK drug database, Molport, SPECS, a database of natural products, etc. The teams will work with viral proteins at the all-atom resolution, they will use molecular dynamics simulations, metadynamics, quantum and molecular mechanics, X-ray crystallography, cryo electron microscopy, nanoparticle detectors, as well as virtual ligand screening, virtual drug design, and other powerful instruments and techniques. The speed and efficiency of these techniques is greatly helped by the huge supercomputing power PRACE provides to the research community.
The PRACE Fast Track Call for Proposals aims to speed up the process from application to outcome. Below you can read a summary of the work each project will undertake.
Read on: Scientific Computing World.
A computational study of the reactivity in the main protease of SARS-CoV-2 to guide the design of inhibitors is led by Prof. Iñaki Tuñón from the University of Valencia, Spain. Over two and a half months, the team will analyse the binding of the substrate and the reaction mechanisms of the main protease of SARS-CoV-2 (the virus strain causing disease COVID-19). The main protease (3CLpro) is an enzyme with essential role during the replication of the virus and is therefore an attractive drug target.
That is why one of the strategies for the development of potential treatments against the SARS-CoV-2 is based on the disruption of the activity of those enzymes that are vital in the replication cycle of the virus, using adequate compounds.
The project led by Prof. Iñaki Tuñón is structured in three work packages and there are five expected outcomes. One of those is the definition of the binding mode of different inhibitors and to propose a chemical modification of the inhibitors to improve their binding to the 3CLpro enzyme. All this supports the overall goal of the team to use the knowledge obtained from the simulation of the catalytic process to guide the design of more potent inhibitors to block the main protease of SARS-CoV-2.
These complex studies require high computational power and PRACE awarded the group with 23 000 000 core hours on the main partition of MareNostrum4, hosted by BSC, Spain, as well as 288 000 core hours on its P9/V100 partition.
Identification of inhibitors of SARS-CoV-2 S protein is a PRACE-awarded project led by Dr Sonsoles Martin-Santamaria from the Spanish Research Council (CIB-CSIC), Spain.
SARS-CoV-2 is the virus strain that causes the disease COVID-19 and the goal of the team is to block the binding of virus spike S to the human cell receptor ACE2, effectively stopping the virus from infecting the cell. The scientists plan to use virtual screening and computational design of peptides to find possible small molecules able to inhibit or block the S protein-mediated fusion mechanism through two processes. Firstly, targeting the protein-protein interface among the monomers (specific molecules), forming the S protein trimer. And secondly, stopping the S protein and ACE2 protein-protein interaction.
The scientists will use the generic drug library (drug repurposing). If they find a promising inhibitory activity to block the coronavirus, these compounds could follow a faster and more direct way through clinical trials. The researchers will also screen antiviral libraries, databases such as ZINC, Molport, SPECS.
All these processes require enormous computational power and PRACE awarded the project with 25 000 000 core hours on Marconi100, hosted by CINECA, Italy.
COVIDYN is led by Dr Himanshu Khandelia from the University of Southern Denmark, Denmark.
The team will drive molecular dynamics (MD) simulations and Markov State Models to block viral entry into the human cells. It happens through an ectodomain of the trimeric S protein of the coronavirus. This domain of a membrane in SARS-CoV-2 is responsible for attachment to and entry into cells during infection.
This project is unique in the sense that it concentrates on the conformational transitions in the S protein that make this binding possible and may point to new drug targets. According to the team, successful viral entry is contingent upon an optimal conformational equilibrium between the „up” (active) and „down” (inactive) conformations of the receptor binding domains (RBDs). They estimate that a lower population of „up” conformations is likely to block the viral entry. The group expects two impressive outcomes from their approach. The first one is to find conformational transitions of the RBDs from the „down” to „up” state for SARS-CoV and SARS-CoV-2. The second is to identify new druggable hotspots that drive these transitions. Therefore, these druggable hotspots can be targets for future antiviral development. Moreover, these studies will be obvious starting points for antibody and antiviral developments.
At the end of the project the scientists want to verify their hypotheses as to why SARS-CoV-2 is more virulent than previous coronaviruses.
All these complex studies and simulations require high computational power and PRACE awarded the team with 35 000 000 core hours on Piz Daint, hosted by CSCS, Switzerland.
Epitope vaccines based on the dynamics of mutated SARS-CoV-2 proteins at all-atom resolution is a PRACE-awarded project led by Prof. Evangelos Daskalakis from the Cyprus University of Technology, Cyprus.
The working hypothesis of Daskalakis’ team is that the research on SARS-CoV-2 should focus on proteins that exhibit higher evolutionary conservation and lower mutation rates as these could be potential drug targets or sources of epitopes. These epitopes, which derive from the spike of the virus, and nucleocapsid proteins, could potentially offer protection against the coronavirus by mapping identically to SARS-CoV-2 proteins. The reason is that epitopes are part of an antigen that is recognized by the immune system, specifically by antibodies, B-cells, or T-cells.
The project’s computational approach advances scientific knowledge on SARS-CoV-2 at the fundamental level. The results will take the form of important protein domains in wild-type, i.e. unchanged, or mutants that could be directly associated with epitopes for eventual vaccines against COVID-19. Of course, they could be further used in protein-drug docking algorithms to predict drug efficiency, and support the engineering of vaccines.
The project focusses on characterising the molecular features associated with the virus (proteins, genetic material) at all-atom resolution. For this the scientists will conduct a screening of a large database of natural products to find potential inhibitors that bind at the key protein domains. They also plan to propose novel molecules as potential inhibitors to block the virus.
All these fundamental studies require enormous computational power and PRACE awarded the project of Prof. Evangelos Daskalakis with 16 000 000 core hours on Joliot-Curie Rome, hosted by GENCI at CEA, France.
A Computational study to guide the development of new SARS-CoV-2 detection hyper-spectral platforms is led by Dr Juan Torras from the Polytechnic University of Catalonia, Spain.
This project focusses on the earliest and fastest detection of the coronavirus causing COVID-19 in patients as well as the understanding of its infection mechanisms. The team is convinced that the knowledge developed in this project will help to obtain novel and better SARS-CoV-2 therapeutics and diagnostics based on antibodies. At the moment PCR tests allow the detection of viral RNA and are the most widely used to diagnose COVID-19. However, according to the group, this type of tests fail in different situations. Simultaneously, antibody tests have a great advantage and they could complement PCR tests.
The team proposes to study silica and gold substrates with different antibodies with classical molecular dynamics. The group will use a nanoparticle (NP) detector for comparative study among different antibodies, their orientation, and their interaction with silica and gold surfaces.
In parallel, the group is working on interactions between antibodies virus spike of the HIV-1 to create novel immunosensor devices. The team is ready to use this experience, all tools, and algorithms in the new COVID-19 project to study the antibody interactions with SARS-CoV-2 spike glycoprotein. Of course, they will use molecular dynamics, quantum mechanics, and molecular mechanics. According to the scientists, combining the new knowledge and results will help to obtain novel and better SARS-CoV-2 therapeutics and diagnostics based on antibodies.
PRACE awarded the project with 40 000 000 core hours on Joliot-Curie KNL, hosted by GENCI at CEA, France.
SPIKE-CAP – Blocking SARS-CoV-2 Spike protein through Computer-Aided design of Peptide inhibitors is a PRACE-awarded project led by Dr Alfonso Gautieri from the Polytechnic University of Milan, Italy.
The SPIKE-CAP project aims to design antiviral peptides (short chains of amino acids, linked by peptide bonds) with ultra-high affinity for the coronavirus spike protein (S) by using high-throughput computational deep scanning mutagenesis. The most promising candidate will be tested by a partner lab at Massachusetts Institute of Technology (MIT) with bio-layer interferometry (BLI) and X-ray crystallography.
Using a computational scanning mutagenesis method, developed at the Polytechnic University of Milan and based on Simulated Annealing Molecular Dynamics, the team will computationally screen peptide mutations and rank them by binding affinity to S protein, while a machine learning algorithm, developed by MIT, will ensure the correct helical folding.
The project has the potential to identify peptides with ultra-high affinity to the spike of the virus, which would outcompete binding with human ACE2, thereby preventing viral infection. The team expects that this project could be helpful for future design of peptidie therapeutics.
To support this innovative approach, PRACE awarded the project with 44 000 000 core hours on Marconi100, hosted by CINECA, Italy.
The project entitled Targeting the Lysosome-Endosome system to avoid virus entry/exit in cells is led by Prof. Matteo Ceccarelli from the University of Cagliari, Italy.
This is an unconventional project with a chance for breakthroughs not only in the battle against the COVID-19, but also for other diseases like cancer and Parkinson. In the project, the team proposes another strategy, less direct, but with a larger potential. It is based on the investigation of an unexplored key target: the lysosomal-endosomal TPC2 ion channels of the two-pore channel family. This system is involved in the trafficking of cells. The lysosome is a small organelle of cells and its interior is an acid to allow molecule degradation by internal enzymes. It has primary importance for many cell processes and it is involved in different diseases, such as cancer and Parkinson, as well as in viral infections. For example, in 2015 it was proven how its inhibition could stop Ebola, and after that, MERS-CoV as well. Therefore, TPC2 is a target with a high potential for the development of antiviral compounds. The team has been working on TPC channels for two years and investigated them by using molecular dynamics and metadynamics simulations. The scientists already started the docking (method for predicting binding of two molecules in stable complex) of a flavonoid of TPC2 as a possible target against cancer.
In their current project they have two main objectives: 1) to understand the mechanism of functioning of TPC2, and 2) its potentiality as a target for antiviral compounds of the flavonoid family. The team expects that they will verify up to five docking sites. It could be a chance not only for discovering antiviral compounds but also for breakthroughs against cancer and Parkinson.
Because the project requires substantial computational power, PRACE awarded the group with 7 920 000 core hours on Marconi100, hosted by CINECA, Italy.
Biomechanic simulations for quantification of the ventilation/perfusion ratio in COVID-19 patients is a PRACE-supported project led by Dr Simone Melchionna from the National Research Council (CNR), Italy.
The project aims at a prognostic judgement of patient management based on the joint usage of pulmonary reconstruction, biomechanical simulations, physiological modelling, machine learning (ML), and artificial intelligence (AI). The project is a result of a collaboration between academic researchers, AI experts, a private entity, medical doctors from radiology, and intensive care units (ICU).
The expected main outcome is to generate predictive values for oxygen and carbon dioxide levels in different ventilation operating scenarios, based on acquired time series, ventilator operating conditions, postures, age, habits, etc. Doctors could evaluate ventilation efficacy specifically to treat severe cases.
Participants in the project consider that the expected results could provide quantitative guidance for ICUs pre-admission and post-admission evaluation, informing clinicians about those patients with comorbidities that require special attention in terms of ventilation operation conditions and manoeuvring. Simultaneously, results of the project could help hospitals quickly set up the new prognostic system, promote the standardisation of work, rationalise the workflow, and improve the efficiency of treatment, as well as medical safety.
To make this project a success, PRACE awarded 30 000 000 core hours on Hawk, hosted by GCS at HLRS, Germany.
Identification and Design of drugs interfering with the host translational inhibitor nsp1 of SARS-CoV2 is a PRACE-supported project led by Prof. Francesco Luigi Gervasio from University College London, United Kingdom.
Gervasio’s team focusses on the fast mutation rate of the virus as a cause of resistance to antiviral drugs and thus requiring a combined therapy targeting different viral genes. The structures of most SARS-CoV2 proteins have been published, including those of widely studied drug targets, such as the interaction between the viral spike (S) protein and its receptor on the human cell surface. In this project, the scientists propose to target a less studied, but equally important non-structural protein 1 (nsp1). This protein has high identity with SARS-CoV nsp1 of around 86%, which has been determined as a major virulence and pathogenicity factor.
Nsp1 inhibits or blocks the cellular innate immune response. It binds to 40S ribosomes to inactivate their translation functions, facilitating efficient viral gene expression in infected cells, and evasion from host immune response.
The aim of this project is to explore the druggability of SARS-CoV-2 non-structural protein 1 and the interaction between nsp1 and the ribosome 40S unit with an experimental screening of compound libraries and drug design. The methods used could provide crucial insights into the rational design and screening of compounds for nsp1 and the nsp1:40S ribosome complex. In so doing, the group will pave the way to a complementary strategy for COVID-19 therapeutics.
PRACE awarded this project with 6 000 000 core hours on Hawk, hosted by GCS at HLRS, Germany.
A drug discovery project against the main protease of COVID-19 is led by Prof. Maria João Ramos from the University of Porto, Portugal.
With this project, she and her team propose to develop drugs for one particular target and this is the main protease of the virus, caused COVID-19. If this main protease enzyme is blocked and it cannot function properly, the virus will not replicate. The process can be facilitated by using available good resolution x-ray structures of this protease in 2020 in the Protein Data Bank.
Subsequently, the scientists will put forward two studies, carried out in parallel to make a list of compounds with anti-virus activity. They will perform Virtual Screening (VS) with protein-ligand docking methodologies to estimate binding sites. They will use protocols and scoring functions and will test not only commercial compound libraries containing millions of compounds, but also their in-house developed compound library, again with millions of compounds. The goal is to identify new chemical entities that can potentially bind to the selected protein target.
Also, the group will identify drugs that must still be active upon the enzyme modifications. This will be done with molecular modelling and molecular dynamics, using Free Energy Perturbation techniques.
PRACE awarded the project with 370 000 node hours on Piz Daint hosted by CSCS, Switzerland.
This article is a summary of the second ten projects that were awarded under the PRACE Fast Track Call for Proposals to mitigate the impact of the COVID-19 pandemic. The summary article of the first ten awarded projects can be found here.