Putting computing power together against SARS-CoV-2

The first vaccines authorised for use are raising hopes for an end to the pandemic. What is still missing, however, is an effective cure. Scientists in the European consortia EXSCALATE4CORONAVIRUS (E4C) and the “Human Brain Project” teamed up with other European research institutions to work on a novel computational approach, reported in a recent publication, by which they identified potent inhibitors of the SARS-CoV-2 main protease, a promising target for antiviral compounds.

“Proteins are not rigid entities,” explains Prof. Giulia Rossetti from the Jülich Institute of Neuroscience and Medicine, Computational Biomedicine, and the Jülich Supercomputing Centre, who led the study. “They are three-dimensional, constantly in motion and extremely flexible. For example, a mutation that is far from the active site can nevertheless substantially alter its plasticity and binding properties.”

In order to identify shapes of the binding site of the main protease that inhibitors might bind to, Rebecca Wade and her group at the Heidelberg Institute for Theoretical Studies (HITS), along with colleagues at Forschungszentrum Jülich and the Stockholm Royal Institute of Technology (KTH), investigated more than 30,000 possible spatial arrangements of the enzyme’s three-dimensional shape.  The HITS researchers applied their TRAPP analysis tool to categorize these “individual snapshots” and identify the best-fitting structures.  These structures were then virtually screened by Giulia Rosetti and her colleagues at Forschungszentrum Jülich.  “It’s like an animated film composed of many individual snapshots,” explains Rossetti. “This way, we calculated which molecules could theoretically fit into all these possible conformations and were able to define a blueprint for high affinity compounds.”

This research demonstrates the value of interdisciplinary trans-European networks and infrastructures, such as EXSCALATE4CORONAVIRUS and HBP, when it comes to pooling expertise and resources and developing new approaches to drug discovery. In further work, the researchers will make use of the Human Brain Project’s FENIX infrastructure.

Publication in ACS Pharmacol. Transl. Sci.https://pubs.acs.org/doi/10.1021/acsptsci.0c00215

Press release Forschungszentrum Jülich