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 M^pro, the accessibility of the solvent, the induced fit and the substrate sequence influence the activity of M^pro. 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 M^pro 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 M^pro and 11-residue peptides derived from the 11 natural cleavage sites. Identification of key interactions between M^pro 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 M^pro. 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.