In March 2020, the World Health Organization declared a global COVID-19 pandemic, and the United Kingdom announced a strict national blockade. When Oxford University scientists returned home, they turned on their computers and began helping develop new drugs targeting SARS-CoV-2, the virus that causes COVID-19.
NS International cooperationWith the participation of 29 scientists from around the world, we focused on understanding how SARS-COV-2 makes worker proteins. Molecular level As a result, we were able to develop a new antiviral drug and block its production. We all work from home, but we meet every week at Zoom to tackle this horrific illness.
“If scientists can design new molecules that bind more strongly than these natural substrates, they can prevent the virus from dying in that pathway. Blocking the cutter blocks the replication of the virus, which is HIV and An effective strategy for the treatment of other viral diseases such as hepatitis, said Professor of Oxford University or Professor Chris Scofield of Chemistry.
Despite the record-breaking successful development of vaccines, there are no drugs specifically designed to target COVID-19, but they are in desperate need.
When SARS-CoV-2 invades healthy human cells, the virus’s own genetic material controls the mechanism of the infected cell, forcing it to make a new copy of the virus.
The new virus begins as one long protein that cleaves itself into functional units. First the cleavage catalyst or “protease” cleaves itself, then it cleaves at multiple other positions.
SARS-CoV-2 has two molecular machines or proteases that resemble “molecular scissors.” The main protease, or one of these, abbreviated as “Mpro,” cleaves at 11 or more of these cleavage sites.
Professor Morris and his collaborators used a 3D structure obtained by irradiating crystals of the major proteases of SARS-CoV and SARS-CoV-2 with a computational model of SARS-CoV-2M. I was able to develop.Professional Bind to that 11 cut site. These models provided important insights into how these viral Ms occur.Professional The work of “molecular scissors”.
“What’s remarkable about this collaboration, which involves 29 scientists from around the world, is that all meetings are fully virtualized and many collaborators haven’t met in person yet.” University of Oxford. Said Professor Garrett M. Morris.
Based on this knowledge, using computational techniques, they then sought to design a new molecule that could bind even stronger than the natural cleavage site.Using a computer to screen out over 200 trillion possibilities, they virus From maturity.
All 11 cleavage sites and 4 of these designed peptides were synthesized and tested in the laboratory of Professor Chris Schofield of the Institute of Chemistry, University of Oxford.Experiments have shown that the newly designed peptide not only binds to the molecular scissors, but also blocks the substrate and actually inhibits M.Professional..
Scientists have also conducted extensive analysis of the hundreds of published 3D structures of small molecules bound to Mpro to predict how inhibitors designed by COVID Moonshot will bind, and these Elucidated how the “molecular key” fits into M’s “molecular lock”Professional, And use these insights to suggest design methods New drug Treat COVID-19.
A huge number of computational techniques were used to build the overall picture of SARS-CoV-2 Mpro, down to comparative molecular modeling. Molecular dynamics, Interactive molecular dynamics virtual reality, Quantum mechanics, Computational peptide design, Protein-ligand docking, Protein-Peptide docking, and Protein-Ligand interaction analysis.
HT Henry Chan et al, Discovery of SARS-CoV-2 Mpro Peptide Inhibitors from Substrate and Ligand Binding Modeling, Chemical science (2021). DOI: 10.1039 / D1SC03628A
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