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Supercomputing against SARS-CoV-2

The first vaccines authorized for use are raising hopes for an end to the pandemic. What is still missing, however, is an effective cure. In the European project EXSCALATE4CORONAVIRUS (E4C), scientists are searching for molecules that block key proteins of the coronavirus. E4C is a public–private consortium backed by the European Commission’s H2020 program that aims at fighting the coronavirus by combining the best supercomputing resources and artificial intelligence with state-of-the-art experimental facilities through to clinical validation.

In a recent publication, the Jülich E4C team headed by Prof. Giulia Rossetti from JSC and the Institute of Neuroscience and Medicine (INM-9) reports a new method to identify inhibitors of “Mpro”, the main protease of SARS-CoV-2. The virus can no longer reproduce if Mpro is inhibited. When searching for drugs, researchers usually follow the lock-and-key principle: they take a library of known molecules, i.e. “keys”, and run a computer test to see which molecule fits into the active-site of the enzyme, the “lock”. The shape of SARS-CoV-2 Mpro, however, turns out to be extremely flexible, meaning that the lock is constantly changing. Therefore, the team reversed the search and started “from the lock side”. Together with colleagues from E4C and the Human Brain Project, the Jülich team investigated more than 30,000 possible spatial arrangements of the active-site, which were used as a “blueprint” to search for the “keys”: with the high-performance computing systems at JSC millions of molecules were screened. Two novel Mpro inhibitors were identified through computer simulations alone. Tests on cell cultures confirmed a moderate antiviral effect. The work appeared in ACS Pharmacology and Translational Science (DOI: 10.1021/acsptsci.0c00215) and reached the cover page.

This research demonstrates the value of interdisciplinary trans-European networks and infrastructures to pool expertise in developing new approaches.

Contact: Prof. Giulia Rossetti, g.rossetti@fz-juelich.de

from JSC News No. 280, 26 April 2021


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