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Towards the discovery of peptides that inhibit the main protease of SARS-CoV-2

The main protease (Mpro) of SARS-CoV-2 plays a central role in virus maturation and is a promising drug target. Little data are available about structural aspects of its binding to its 11 natural cleavage sites. We used [collaboration] biophysical and crystallographic data as well as a set of biomolecular simulation techniques (automated docking, virtual reality molecular and interactive dynamics, QM/MM, and linear scale DFT) to investigate the molecular features underlying the recognition of natural substrates of Mpro.

Published on 24 September 2021
A key step in the maturation of SARS-CoV-2, an RNA virus, is hydrolysis of some of its proteins by Mpro, its main protease. The role of this molecular scissor is to make cuts at no less than 11 sites. Important questions remain, such as how the protonation state of the active site of Mpro, the accessibility of the solvent, the induced fit and the substrate sequence influence the activity of Mpro. The lack of this knowledge makes it difficult to perform effective computational studies of the catalysis and inhibition of this protease. If new molecules could be designed that bind more tightly than these natural substrates, then it would be possible to stop the virus. Blocking Mpro would prevent the virus from replicating.

In an effort to contribute to the fight against Covid-19, we embarked on a collaborative effort in April 2020 and utilized a combination of classical molecular mechanics (MM) and quantum mechanics (QM) techniques, including automated non-covalent and covalent docking, molecular dynamics (MD) simulations, density functional theory (DFT), combined quantum mechanics/molecular mechanics (QM/MM) modeling, and interactive MD in virtual reality (iMD-VR). We have analyzed in detail the interactions between subsites of modeled 11-residue cleavage site peptides, crystallographic ligands and covalent inhibitors designed by COVID Moonshot.
Our results provide atomic-level consensus insight into the interactions between Mpro and 11-residue peptides derived from the 11 natural cleavage sites. Identification of key interactions between Mpro and its substrates, as well as analysis of fragment/inhibitor structures, led to the design of peptides proposed to bind more tightly than natural substrates, several of which inhibit Mpro. The results are freely available via GitHub.
"What is remarkable about this collaboration, involving 29 scientists from around world, is that every meeting was entirely virtual, with many collaborators yet to meet face-to-face". Luigi Genovese, MEM Laboratory, IRIG, CEA-Grenoble.
Chemistry Research Laboratory, Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, UK
Department of Statistics, University of Oxford, UK
Centre for Computational Chemistry, School of Chemistry, University of Bristol, UK
Intangible Realities Laboratory, School of Chemistry, University of Bristol, UK
School of Biochemistry, University of Bristol, UK
RIKEN Center for Computational Science, Kobe, Japan
Diamond Light Source Ltd, Harwell Science and Innovation Campus, Didcot, UK
Research Complex at Harwell, Harwell Science and Innovation Campus, Didcot, UK
Biocomp Group, Institute of Advanced Materials (INAM), Universitat Jaume I, Spain
Food and Drug Department, University of Parma, Italy
Univ. Grenoble Alpes, CEA, IRIG-MEM-L_Sim, Grenoble, France

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