The EXSCALATE4CoV (E4C) project aims to exploit the most powerful computing re-sources currently based in Europe to empower smart in-silico drug design. Advanced Computer-Aided Drug Design (CADD) in combination with the high throughput bio- chem-ical and phenotypic screening allows the rapid evaluation of the simulations results and the reduction of time for the discovery of new drugs. 

Against a pandemic crisis, the immediate identification of effective treatments has a paramount importance. First, E4C selected through the Dompé EXSCALATE platform, the most promising commercialized and develop-ing drugs safe in man. Second, selected from >500 billion molecules new pan coronavirus inhibitors. 

Huge computational resources are needed, therefore the activities are supported and empowered by four of the most powerful computer centres in Europe: CINECA, BSC, JÜLICH and Eni HPC5. The Swiss Institute of Bioinformatics (SIB) provides the homology 3D models for the viral proteins. The Fraunhofer IME provides the BROAD Repurposing Library and biochemical assays for the most relevant viral proteins. Phenotypic screenings have been run by KU LUEVEN to identify molecules capable of blocking virus replication in in-vitro models. IIMCB and ELECTRA determines the crystal structure of at least one coronavirus functional proteins to evaluate the structural similarities with other viral proteins. 

All the other partners support the project by studying the mechanism of action, synthetizing the most relevant candidate drugs and enhancing the HPC and AI infrastructure of the consortium. The worldwide biggest virtual screening simulation was performed by evaluating more than 1 Trillion molecular docking. Chelonia leads the communication and dissemination activities. 

EXSCALATE4CoV consortium identified safe in man drugs repurposed as 2019-nCoV antiviral and proposed to the EMA innovation task force (ITF) to define a preliminary development strategy and a proposal for a registration path. The E4C project shared promptly its scientific outcomes with the research community by using established channels: ChEMBL portal for the biochemical data, the SWISS-MODEL portal for the homology mod-els of viral proteins WT and mutants, the Protein Data Bank, the EUDAT for the data generated by in-silico simulations and the E4C project website. 

Combining HPC simulations and AI driven system pharmacology E4C has identified and in vitro experimentally validated a first promising drug for the treatment of mildly symptomatic Covid19 patients. Raloxifene Phase II clinical trial was completed in July 2021. The Spallanzani hospital is the Coordinating Investigator in the clinical trial. Several initiatives have been launched in the framework of E4C as well as MEDIATE also supported by SAS, SPIKE MUTANTS, VIRALSEQ and DRUGBOX. All of them are accessible through the main web portal.