A new virtual screening strategy identifies the existing drug that inhibits the Covid-19 virus

IMAGE: Color scanning electron micrograph of an apoptotic cell (pink) heavily infected with SARS-COV-2 virus particles (green), isolated from a patient sample. Image captured at NIAID Integrated Research Facility (IRF) … view More

Credit: National Institute of Allergy and Infectious Diseases / NIH, 2020 (CC0)

A new computerized drug screening strategy, combined with laboratory experiments, suggests that pralatrexate, a chemotherapy drug originally developed to treat lymphoma, could be reused to treat Covid-19. Haiping Zhang of Shenzhen Institutes of Advanced Technology in Shenzhen, China and colleagues present these findings in the open access journal PLOS Computational Biology.

Given that the Covid-19 pandemic causes disease and death worldwide, better treatments are urgently needed. A shortcut could be the reuse of existing drugs that were originally developed to treat other conditions. Computational methods can help identify these drugs by simulating how different drugs would interact with SARS-CoV-2, the virus that causes Covid-19.

To help virtual screening of existing drugs, Zhang and colleagues combined several computational techniques that simulate drug-virus interactions from different, complementary perspectives. They used this hybrid approach to examine 1,906 existing drugs for their potential ability to inhibit SARS-CoV-2 replication by targeting a viral protein called RNA-dependent RNA polymerase (RdRP).

The new screening approach identified four promising drugs, which were then tested against SARS-CoV-2 in laboratory experiments. Two of the drugs, pralatrexate and azithromycin, successfully inhibited the replication of the virus. Other laboratory experiments have shown that pralatrexate inhibits viral replication more strongly than remdesivir, a drug currently used to treat patients with Covid-19.

These findings suggest that pralatrexate may be reconstituted for the treatment of Covid-19. However, this drug for chemotherapy can cause significant side effects and is used for people with terminal lymphoma, so immediate use for patients with Covid-19 is not guaranteed. However, the findings support the use of the new screening strategy to identify drugs that could be reused.

“We have demonstrated the value of our new hybrid approach that combines deep learning technologies with more traditional simulations of molecular dynamics,” says Zhang. He and his colleagues are now developing additional computational methods to generate new molecular structures that could be developed into new drugs to treat Covid-19.

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Evaluated by colleagues; Simulation / modeling

In your coverage, please use this URL to provide access to the free article available in PLOS Computational Biology:
http: // journal.PLoS.org /ploscompbiol /article? id =10.1371 /diary.pcbi.1008489

Citation: Zhang H, Yang Y, Li J, Wang M, Saravanan KM, Wei J et al. (2020) A new virtual screening procedure identifies Pralatrexate as an inhibitor of SARS-CoV-2 RdRp and reduces viral replication in vitro. PLoS Comput Biol 16 (12): e1008489.
https: //two.org /10.1371 /diary.pcbi.1008489

funding: This work was partially supported by China’s Key National Research and Development Program under grant no. 2018YFB0204403 (YW) and 2019YFA0906100 (XW); Strategic Priority CAS Project XDB38000000 to YW, National Science and Technology Major Project under Grant No. 2018ZX10101004 (YY), National Science Foundation of China under Grant no. U1813203 (YW); National Foundation for Natural Sciences of China (Grant no. 31601028: YP); Shenzhen Basic Research Fund from grant no. JCYJ20190807170801656 (JL), JCYJ20180507182818013 (YW), JCYJ20170413093358429 (YW) and the SIAT Innovation Program for Young Excellent Researchers (JL). Funders had no role in designing the study, collecting and analyzing the data, publishing decision or preparing the manuscript.

Concurrent interest: No author has competing interests.

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