March 6, 2020 — Italian-based consortium Exscalate4CoV (E4C) was awarded €3 million (~$3.39 million) by the European Commission for research projects focusing on the Coronavirus under the Horizon 2020 framework program.
The primary objective of E4C is to exploit the potential of supercomputing combined with life science scientific skills in Europe to better and quickly face pandemic situations of supranational interest.
At the center of the project is Exscalate (EXaSCale smArt pLatform Against paThogEns), the supercomputing system – High Performance Computing, Structure-Based Drug Design System – operating globally thanks to its “chemical library” of 500 billion molecules, capable of evaluating more than three million molecules per second.
The consortium, led by pharmaceutical Dompé, aggregates 18 institutions and research centers in seven European countries including Politecnico di Milano (Department of Electronics, Information and Bioengineering), CINECA Interuniversity Consortium (Supercomputing Innovation and Applications), University of Milan (Department of Science Pharmaceuticals), Katholieke Universiteit Leuven, International Institute Of Molecular And Cell Biology In Warsaw ( LIMCB ), Electra Italian Crystallographic Association, Fraunhofer Institute for Molecular Biology and Applied Ecology , Bsc Supercomputing Center, Forschungszentrum Jülich, Federico II University of Naples, University of Cagliari, SIB Swiss Institute of Bioinformatics, KTH Royal Institute of Technology (Department of Applied Physics), BigData Association, National Institute of Nuclear Physics (INFN), the National Institute for the infectious diseases Lazzaro Spallanzani and Chelonia Applied Science.
More specifically, the project aims to identify the safest and most promising drugs for the immediate treatment of the already infected population, followed by the identification of molecules capable of inhibiting the pathogenesis of coronavirus to counter future contagions.
The plan of E4C is structured as follows:
- Establish a sustainable scientific standard to give quick answers to any pandemic scenario. The model is based on the use of a supercomputing platform integrated with artificial intelligence systems, 3D modeling supported by X-ray diffractometry for the identification of the best candidates for the clinic and subsequent validation of laboratory experimentation on predictive cell models (viruses, bacteria, etc.);
- Identify virtually and quickly the drugs available, or at an advanced stage of development, potentially effective;
- Define a screening model to validate potentially effective molecules and any pathogen action and mutation mechanisms;
- Structuring together with EMA – European Medicine Agency – an effective experimentation model on the molecule identified to speed up its time for therapeutic use;
- Identify the genes involved in the development of the pathology.
The EXSCALATE platform will be dedicated to identifying the most promising molecules to combat coronavirus thanks to the ability to combine the design of in silico drugs and a virtual library of 500 billion “tangible” (easy to synthesize) compounds.
The CINECA, BSC and Jülich supercomputing centers will perform all the molecular dynamics simulations of viral proteins and the ultra-fast virtual screening of the E4C library.
The University of Milan (UNIMI) and the Polytechnic of Milan (POLIMI) will be engaged respectively in support of the virtual screening activity and for the acceleration of the computational process.
The results of the virtual screening will culminate in the selection of active compounds to be tested in the phenotypic screening phase at the Katholieke Universiteit Leuven research infrastructure through a multiparametric high throughput screening (High Throughput Screening) platform on live pathogens at high biosecurity risk ( level 3) or unknown.
The Fraunhofer Institute for Molecular Biology and Applied Ecology (IME) will integrate phenotypic screening with the biochemical assay on the targets of the various putative viruses, through access to Fraunhofer’s BROAD Repurposing Library.
The University of Cagliari (UNICA) will complete the biological evaluation defining the mechanism of action of the inhibitors and the selection of the mutants in the systems. This information will be crucial to define the genetic barriers of potential drugs and to select the most promising molecules to be developed. The Italian Crystallography Association (AIC) and the International Institute of Molecular and Cellular Biology (IIMCB) will produce X-ray structures for the most interesting viral enzymes and related inhibitors in order to support the rational design of new chemical structures capable of inhibit Coronaviruses. The Medical Chemistry team of the University of Naples Federico II (UNINA) will support the EXSCALATE team in the selection of the best compounds, as well as taking care of the chemical synthesis of the best candidates.
For more information:
Cineca is a not-for-profit Consortium, made up of the Italian Ministry of Education Universities and Research, 69 Italian universities, 11 Italian National Institutions (8 Italian Research Institutions, 2 Polyclinics, 1 National Agency). Today it is the largest Italian computing center, one of the most important worldwide. With more than seven hundred employees, it operates in the technological transfer sector through high performance scientific computing, the management and development of networks and web-based services, and the development of complex information systems for treating large amounts of data. It develops advanced Information Technology applications and services, acting like a trait-d’union between the academic world, the sphere of pure research and the world of industry and Public Administration.