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EXaSCale smArt pLatform Against paThogEns for Corona Virus

Periodic Reporting for period 1 - EXSCALATE4CoV (EXaSCale smArt pLatform Against paThogEns for Corona Virus)

Reporting period: 2020-04-01 to 2021-03-31

Exscalate4CoV (E4C) project addressed a globally unmet societal and medical need: is there an infrastructure/operating workflow that might help in quickly identifying existing or new drugs in case of a pandemic outbreak? Under these premises, E4C has been of the highest societal importance. Given that the pandemic we are living in is one of the most serious issues of health in the world, which need to be transacted, the project addressed these public health issues. This private-public consortium has developed a realistic and fast operational workflow to give a quick scientific answer to this pandemic crisis. In-Kind contributions from private pharma R&D allowed E4C scientists to have access to newly developed simulation technologies. The parallel and integrated effort in structural biology, biochemistry, and cellular biology to identify old drug (repurposing) and novel chemical entities easy to synthesize was coupled, in an unprecedented way, to the provided IT technology with the ambition to as quick as possible deliver validated candidate drugs to public health officers such as EMA and hospitals.
The Computational-Aided Drug Design technologies applied during Phase 1 of the project, led to fast virtual identification of known drugs (repurposing). After the experimental validations, the most promising one, the Raloxifene, is in clinical trials, and the other 3 molecules were selected as clinical candidates. Also, the experimental test activities led to the development of 4 biological assays and to the test of 20,000 molecules of which 348 were found to be active.
Thanks to in silico technologies such as molecular dynamics simulations, it was possible to evaluate and understand the structural behavior of over 45 viral proteins. In particular, in the initial phase of the pandemic, given the lack of experimental protein models, a web platform was created for the generation of homological models of viral proteins, useful for the entire scientific community (https://swissmodel.expasy.org/). This allowed the entire scientific community to get access to these outstanding data.
Then, the collaboration between the project Partners and the entities belonging to the Exscalate4CoV’s League, more than 35 viral proteins have been identified and experimentally solved, using X-ray techniques, allowing us to include high-quality structural information into our computational studies.
In November 2020, the beginning of Phase 2 was preceded by the largest virtual screening experiment ever carried out. This unprecedented simulation involved the two supercomputers of ENI and CINECA, and allowed to virtually test over 1 Trillion molecules against the most important viral proteins, in just 60 hours. This result confirms the real possibility of exploiting HPC platforms in cases of pandemics.
The impressive amount of data produced from the simulation was processed in collaboration with SAS, using artificial intelligence techniques and advanced analytics. Results are available on the portal 1trilliondock.exscalate4cov.eu and then on the portal mediate.exscalate4cov.eu co-designed with SAS to allow scientists around the world to carry out their own molecular docking simulations, benefiting from "state of the art" knowledge supplied by E4C project through the MEDIATE initiative.
To date, this initiative (MEDIATE - MolEcular DockIng AT home) - will give free access to the largest database available today on the Sars-CoV-2 Virus both from a structural (three-dimensional structures) and functional (proteins interacting with human cells) point of view, including all the molecular dynamics involved in cellular interaction and active sites for potential drug entry.
The huge amount of experimental and theoretical data produced within the project led to the publication of 29 peer review papers with a global impact factor > 154 points in 1 single year (of which around 50 impact factor points achieved since January 2021) and the achievement of 3 patents, underlining the high quality of the results produced till now. Other scientific works are in preparation and some of them were already submitted or are in the revision phase.
In addition to the project activities planned and completed over the course of one year, E4C has strengthened the process of making data and information available to support the entire scientific community engaged in the fight against Sars-CoV-2. In particular, two websites have been launched that will provide important information regarding the monitoring and study of mutations in viral proteins and related variants of the virus.
In https://viralseq.exscalate4cov.eu/ the viral mutations retrieved using genomic data from public repositories (i.e. GISAID, EMBL COVID-19 data portal) are mapped and analyzed in their 3D structural context to investigate their impact in terms of host-immune interaction, ligand/substrate/drug binding sites and SDPs. Together with WP5 and WP7, we are collecting all this essential information and making it easily usable and accessible to the scientific community and beyond.
The other web portal is https://spikemutants.exscalate4cov.eu/ that aims to provide the scientific community with structural information on emerging variants involving the protein sequence of the Sars-CoV-2 Spike protein. The website will also include data and results coming from MD simulations and analysis of Spike-Antibody complexes. While these two websites are already up and running, two more web platforms will be launched in the next two weeks and will be the Apriori website (Activity PRedIction Of youR lIgand) that freely provide docking-based predictive models involving the relevant non-structural (NSP) viral targets. The website will be enhanced continuously by also including predictive models for the most important mutants retrieved. The other impressive release will be https://sc2md.exscalate4cov.eu/ a website that include MD trajectories retrieved worldwide and analysis tools to better understand the dynamic behavior of viral proteins.
In July the Raloxifene clinical trial will be concluded and in case of success the consortium discovered and clinically validate a molecule ready to be used in patients these activities have been funded by an additional EU H2020 Grant the COVIRAL project.
1 Trillion docking experiments workflow
Making data and information available to support the entire scientific community
The Exscalate4COV's Consortium18 institutions from 7 European countries