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First appearing in late 2019, the SARS-CoV-2 virus continues to cause sickness and death across the globe. Researchers and scientists have been looking at multiple solutions to treat COVID-19, including repurposing approved pharmaceutical drugs. This research points to very promising treatment options. A team of researchers at the Pritzker School of Molecular Engineering (PME) at the University of Chicago used state-of-the-art computer simulations to identify how a preexisting drug could fast-track a solution to this worldwide pandemic. Their findings appear in a paper published August 14 in the journal Science Advances.
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 coronavirus 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 is a chemical compound with anti-viral, anti-inflammatory, anti-oxidative, bactericidal, and cell-protective properties. Ebselen is used to treat multiple diseases, including bipolar disorders and hearing loss. Several clinical trials have proven its safety for use in humans.
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. “In addition to binding at the catalytic site of the enzyme, Ebselen also binds strongly to a distant site, which interferes with the enzyme’s catalytic function by relying on a mechanism in which information is carried from one region of a large molecule to another region far away from it through subtle structural reorganizations,” de Pablo said. That finding was particularly important because it helped explain Ebselen’s potential efficacy as a repurposed drug, and it revealed a new vulnerability in the virus that was previously not known and that could be use useful in developing new therapeutic strategies against COVID-19.
Published in Science Advances (August 14, 2020):
