From virtual screens to promising inhibitors of coronaviruses: An effort to develop an antiviral drug to treat COVID-19

From virtual screens to promising inhibitors of coronaviruses: An effort to develop an antiviral drug to treat COVID-19

Researchers from Uppsala University have identified a molecule that can be developed into a drug to treat COVID-19. The molecule was discovered by using structure-based virtual screening and has a strong ability to inhibit both SARS-CoV-2 replication and the previously known variants of the coronavirus. This research was a part of the SciLifeLab and KAW national COVID-19 research program.

The COVID-19 pandemic has caused the death of more than six million people worldwide (WHO: May 2022). Even when the world was at a halt, scientists worked to develop treatments for the disease.

Starting in 2020, researchers from Uppsala University and the SciLifeLab Drug Discovery and Development platform used supercomputers to identify inhibitors based on the molecular structure of the main protease, which is a key element in the replication of the coronavirus. The goal was to design a molecule that inhibits the activity of the main protease by blocking its active site. It would prevent the virus from infecting other cells, stopping the spread of the disease. The same approach is used to treat HIV and Hepatitis C.

Andreas Luttens (first author) in one of the team discussion on the subject.

After screening 235 million virtual molecules against the active site, the researchers synthesized and tested 193 compounds in experiments. Eight inhibitors were discovered, and X-ray crystallography confirmed the predicted binding modes for five of these.

Hit optimization resulted in a promising lead with high affinity for the enzyme, drug-like properties, and potent antiviral effect against several coronaviruses.

MAX IV’s BioMAX beamline determined the crystal structures in the study. “Biomax beamline and scientists that helped us get structures of our inhibitors in complex with the enzyme were crucial for the project, said Jens Carlsson, one of the researchers involved.


On track towards an antiviral drug

Carlsson hopes that the designed molecule can be further developed into an antiviral drug, which will complement the available vaccines. An antiviral drug could be important for unvaccinated risk groups, individuals with severe symptoms despite being vaccinated, and to prepare for future coronavirus pandemics.

Currently, the research team is modifying some of the molecule’s properties to make it suitable as a drug and searching for collaboration partners in the pharmaceutical industry.

“We have received research funding to continue to optimize the compounds during 2022, and our goal is to find a partner by the end of the year that can help us develop an antiviral drug. We are currently discussing our project with several potential collaborators,” said Carlsson.



Andreas Luttens et al. Ultralarge virtual screening identifies SARS-CoV-2 main protease inhibitors with broad-spectrum activity against coronaviruses, J. Am. Chem. Soc. 2022, 144, 2905-2920. DOI: