In the race to find potential treatments for SARS-CoV-2, the virus that causes COVID-19, researchers have often focused on how to disrupt the functional proteins on the virus’s active binding site — the spike that binds to human cells.
But using simulations, researchers at the Pritzker School of Molecular Engineering (PME) at the University of Chicago have found a different way to disrupt the virus: through compounds that bind at a previously unidentified distant binding site (far from the main active site) of one of the virus’ proteins, thereby destabilizing it and inhibiting its ability to replicate.
They also found that an existing natural compound, luteolin, interacts in this way with the SARS-CoV-2 virus.
“Understanding this mechanism could pave the way for future drug discovery,” said Prof. Juan de Pablo, who led the research. The results were published in the journal Molecular Systems and Design Engineering.
Using computer simulations to understand potential treatments
Since the beginning of the pandemic, de Pablo and his group have been using advanced computational simulations to systematically look at the different proteins that allow the virus to replicate or infect cells. They also have looked at key drugs that are already used to treat other diseases and could be repurposed to inhibit those processes in SARS-CoV-2. The simulations, which require months of extremely powerful computations, ultimately reveal what happens to the virus at the molecular level.
Previously, the group used computational analysis to reveal how the drug Ebselen binds to the virus’s main protease, or MPro. In a different study, they also revealed how the antiviral drug remdesivir binds to and interferes with the virus.
In this new research, they used molecular simulations to decipher how compounds bind to the virus and lead to an allosteric effect, which means they produce changes throughout the virus, not just at the binding site. These changes propagate throughout the protein and inhibit its ability to form complexes with other proteins, making the virus less efficient and hindering its ability to replicate.