Since appearing in late 2019, the SARS-CoV-2 virus has caused sickness and death across the globe. Researchers and scientists have been looking at multiple solutions to treat COVID-19, including repurposing approved pharmaceutical drugs. One such preexisting drug that offers promise as a possible treatment option is called Ebselen.
A team of researchers at the Pritzker School of Molecular Engineering at the University of Chicago used state-of-the-art computer simulations to explain how Ebselen may counteract the virus. Their findings, which could help provide new avenues to boost Ebselen’s effectiveness as well as suggest approaches for other drugs, appear in a paper published August 14 in the journal Science Advances.
Mpro versus Ebselen
Early in February, concerned by the rapid progress of the pandemic, Prof. Juan de Pablo and his students used their molecular modeling expertise to help find a treatment against the disease. They were not the only ones. Other groups around the world were beginning to use supercomputers to rapidly screen thousands of existing compounds for potential use against the SARS-CoV-2 virus.
“By virtue of the large number of compounds considered in high throughput screens, those calculations must necessarily involve a number of simplifications, and the results must then be evaluated using experiments and more refined calculations,” explained de Pablo, the Liew Family Professor of Molecular Engineering.
Researchers first focused on finding a weakness in the virus to target. They chose its main protease: Mpro. Mpro is a key enzyme that plays a central role in the virus’ life cycle. It facilitates the virus’ ability to transcribe its RNA and replicate its genome within the host cell.
A pharmaceutical drug that shows promise as a weapon against Mpro is Ebselen. Ebselen, a chemical compound with anti-viral and anti-inflammatory properties, is already used to treat multiple diseases, including bipolar disorders and hearing loss. Clinical trials have evaluated its safety for use in humans.
How it works
de Pablo and his students set out to develop detailed models of the enzyme and the drug. Using those models and sophisticated supercomputer simulations, they discovered that the small Ebselen molecule is able to decrease Mpro’s activity in two different ways.
Mpro works by cutting up specific pieces of virus so that it can replicate itself; Ebselen binds to not only one, but at least two sites, and prevents Mpro from working.