Advanced CADD, in combination with the high throughput biochemical and phenotypic screening, will allow the rapid evaluation of the simulation results and the reduction of time for the discovery of new drugs. This approach is especially useful against pandemic viruses and other pathogens, where the immediate identification of effective treatments is of paramount importance. First, E4C will select, through the EXSCALATE platform and the virtual screening protocols, the most promising drugs against coronavirus taken from the commercialized and developing drugs safe for humans (> 10000 drugs, SIM). At the same time, the proprietary Tangible Chemical Database (TCDb), comprising > 500 billion molecules, will be screened to identify new potential drugs to be tested against coronavirus, thus enhancing the success rate of the virtual screening step.
The aim of E4C is twofold: to identify molecules capable of targeting the coronavirus (2019-nCoV) and to develop an effective tool for countering future pandemics to be consolidated over time.
More specifically, E4C aims to:
- Establish a sustainable example for a rapid scientific response to any future pandemic scenario. The model leverages a rapid and effective High Performance Computing platform for the generation and analysis of 3D models and experimental 3D structures, X-ray resolution of protein targets from pandemic pathogens.
- Drive a fast virtual identification and repurposing of known drugs or proprietary/commercial candidate molecules to be further experimentally characterized.
- Define a workflow scheme for biochemical and cellular screening tests to validate candidate molecules at previous points and assure through phenotypic and genomic assays.
- Prepare, together with EMA, a development plan for successful candidates for direct “first in human” type studies or for further testing in animals with bridging studies.
- Identification of 2019-nCoV genomic regions involved in host adaptation, pathogenicity and mutations.
To further accelerate the identification of drugs by the E4C for the next pandemic, SIB will provide an automated, scalable, robust, well-documented, and benchmarked workflow that produces annotated homology models directly from the sequenced genome of the virus. The generated models will enable the efficient analysis and interpretation of the viral protein products and will be immediately available on the EXSCALATE platform for virtual screening. Such massive virtual screening activities need a huge computational resource, therefore the activities will be supported and empowered by three of the most powerful computer centers in Europe namely CINECA, BSC and JÜLICH. These three Tier-0 supercomputing centers will be able to jointly guarantee the best combination of hardware architectures, required knowledge and the highest speed-up for the simulations.
In addition, INFN (CERN Tier-1 center) will make their data sharing and high throughput infrastructure available to facilitate product exploitation.
As knowledge-based system, the E4C project will take advantage of the SIB infrastructure especially for the phylogenetic, co-evolutive and pathogenicity aspects of the viral key bioinformatic characterizations (i.e. RNA and protein sequences).
The considerable amount of sequence information coming from all scientific communities and hospitals will be surely captured by consolidated pipelines of several public databases. The E4C Consortium will refer to SIB and its network to get the latest sequence data and analyses.
The E4C project will promptly share its scientific outcomes with the research community by using established channels like the ChEMBL portal for the biochemical data, the SWISS-MODEL portal for the homology models of viral proteins WT and mutants, the Protein Data Bank for the experimentally resolved protein structures, the EUDAT for the data generated by in silico simulations, and the E4C project website.