A team of researchers from the University of Chicago’s Pritzker School of Molecular Engineering (SME) used computer simulations to identify a pre-existing drug that could drive the solution to this global pandemic.
Their findings appear in the article, “Molecular characterization of Ebselen’s binding activity to SARS-CoV-2 main protease four,” which was published on August 1 in the journal Science Advances.
Mpro vs. Ebselen
In early February, involved in the immediate progression of the pandemic, Professor Juan de Pablo and his academics used their experience in molecular models to locate a cure for the disease. They weren’t the only ones. Other teams around the world were starting to use supercomputers to temporarily select thousands of existing compounds for potential use opposite SARS-CoV-2.
“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,” de Pablo explained.
Researchers first focused on locating a weakness in the virus to attack. They chose their main protease: Mpro. Mpro is a key coronavirus enzyme that plays a central role in the life cycle of the virus. It facilitates the virus’s ability to transcribe its RNA and reflect its genome in the host cell.
Ebselen is a promising pharmaceutical drug as a weapon opposite Mpro. Ebselen is a chemical compound with antiviral, anti-inflammatory, antioxidant, bactericidal and cell-protective properties. Ebselen is used to treat various diseases, bipolar disorder and hearing loss. Combined with money, Ebselen treats five clinically unwieldy, antibiotic-resistant Gram-negative bacteria. Several clinical trials have proven its protection in humans.
How it works
Paul and his academics set out to expand detailed models of the enzyme and drug. Using these models and complicated supercomputer simulations, they found that Ebselen’s small molecule minimizes Mpro’s activity in two other ways.
“In addition to joining the enzyme catalytic site, Ebselen also strongly binds to a remote site, which interferes with the catalytic function of the enzyme depending on a mechanism in which data is transported from a region of a giant molecule to a remote region. . away from him through sophisticated structural reorganizations, ” says of Paul.
This discovery was critical because it helped Ebselen’s prospective efficacy as a reused drug and revealed a new vulnerability in the virus that was unknown in the past and can be useful in the progression of new healing methods opposed to COVID-19.
Working day and night, the team finished their paintings in just over two months and sent their manuscript to the public archives in April for further examination.
Pharmacological potential
The team’s discovery of two binding sites looks promising for Ebselen to be a leading new drug for the design and progression of new Mpro inhibitors and COVID-19 treatment. Motivated by their discoveries, Paul and his student are quick to point out that much remains to be done.
“Main protease is one of many viral proteins that can be attacked with existing and reused drugs, and there are thousands of compounds to consider,” Paul says. “We systematically examine the proteins involved in the virus service and examine their vulnerabilities and responses to a wide range of medicines.”