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EXaSCale smArt pLatform Against paThogEns for Corona Virus

Periodic Reporting for period 2 - EXSCALATE4CoV (EXaSCale smArt pLatform Against paThogEns for Corona Virus)

Reporting period: 2021-04-01 to 2021-09-30

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). Raloxifene’s clinical trial with 150 patients in 3 EU countries, has been completed, and the other 3 molecules were selected as clinical candidates. Also, the experimental test activities led to the development of 12 biological assays and to the test of 70000 molecules (+50000 and 20000 within E4C and COVIRAL project rspectively) of which 600 were found to be active.
Thanks to in silico technologies such as molecular dynamics simulations, we deployed precious web platforms to support the global research community with bioinformatics and simulation tools. The most complete (> 60 simulations) and the most informative (> 10 µs) set of SARS-COV-2 molecular dynamics simulations were released thanks to the best European HPC resources. 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.
Experimental and theoretical data produced within the project led to the publication of 38 peer review papers with a global impact factor > 200 points 18 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.
While https://viralseq.exscalate4cov.eu/ and https://spikemutants.exscalate4cov.eu/ are already up and running, two more web platforms has been launched. Apriori website (Activity PRedIction Of youR lIgand), https://apriori.exscalate4cov.eu/ that freely provide docking-based predictive models involving the relevant non-structural (NSP) viral targets. The websites will be enhanced continuously by also including predictive models for the most important mutants retrieved. The other impressive release will be http://SCoV2-MD.org a website that include MD trajectories retrieved worldwide and analysis tools to better understand the dynamic behaviour of viral proteins. Related scientific paper was published on Nucleic Acids Research, one of the most important worldwide journal taking care of biochemistry and molecular biology.
The clinical trial on Raloxifene with 150 patients in 3 EU countries has been completed, and other 3 clinical candidates were identified.
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