The study, published in the journal Science Advances, evaluated the molecule main protease, Mpro, of the novel coronavirus, which is a key enzyme that plays a central role in its life cycle.
According to the researchers, including those from the University of Chicago in the US, Mpro enables the virus’ ability to make proteins from its genetic material – RNA – and enables the pathogen to replicate within the host cell.
Using their expertise in modeling biological molecules, the scientists quickly researched thousands of existing compounds for potential use against the virus.
“Because of the large number of connections considered in high-throughput screens, those calculations must necessarily include a number of simplifications, and the results must then be evaluated with experiments and more sophisticated calculations,” explained study co-author Juan de Pablo of the University of Chicago .
They found that the pharmaceutical medicine that shows promise as a weapon against Mpro is Ebselen – a chemical compound with anti-viral, anti-inflammatory, anti-oxidative, bactericidal and self-protective properties.
According to the researchers, Ebselen is used to treat multiple diseases, including bipolar disorder and hearing loss.
They said several clinical trials have proven their safety for use in humans.
In the research, Pablo and his team developed detailed models of the enzyme and the medicine, and with versatile supercomputer simulations, they discovered that Ebselen is able to reduce the Mpro’s activity in two different ways.
“In addition to binding to the catalytic side of the enzyme, Ebselen also strongly binds to a remote site, which interferes with the catalytic function of the enzyme by relying on a mechanism in which information is extracted from one region of a large molecule. to another region away from it by subtle structural reorganizations, “said Pablo.
According to the scientists, this finding is particularly important because it helps to explain the potential effectiveness of Ebselen as a repurposed drug, and revealed a new vulnerability in the virus that was not previously known and that may be useful in developing new therapeutic strategies against COVID-19.
While the researchers believe further studies are needed to test the drug against COVID-19, they believe the two binding sites on Mpro promise Ebselen to be a new drug leader.
“The major protease is one of many proteins in the virus that can be targeted with existing, reimbursed drugs, and there are thousands of compounds that need to be considered,” Pablo said.
“We systematically examine each of the proteins involved in virus function and examine their vulnerabilities and their responses to a wide range of drugs,” he added.
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