A computational study of 4,600 drugs indicates that approved drugs were less effective than non-approved drugs when binding to a COVID-19 protein. In addition, Diosmin, a non-prescription natural supplement bound better than 99% of drugs considered.

HOUSTON, TX, April 21, 2020 /Neptune100/ — A researcher at NXG Logic, LLC (www.nxglogic.com) recently completed a molecular dynamics study of 4,600 drugs to identify which ones could potentially be repurposed to treat COVID-19 disease. The findings are described in a preprint titled “In Silico Molecular Dynamics Docking of Drugs to the Inhibitory Active Site of SARS-CoV-2 Protease and Their Predicted Toxicology and ADME,” which provides a full description of the computational approach pursued and is being submitted for peer-review.

COVID-19 disease is caused by the newer form of the earlier 2003 SARS-CoV virus, called SARS-CoV-2. Both variants of the virus are zoonotic, meaning they originated from animal sources. The investigator, Dr. Leif Peterson, said that “because of mutations in the newer SARS-CoV-2 virus, almost everything must be re-studied, including the search for new drugs and vaccines.” If the mutations observed in the virus don’t seem to change that much as it moves across the globe – it will lead to consistency, meaning that drugs and vaccines may work for a wider patient population.

“While existing drugs, such as antivirals, may be effective for treating the earlier SARS disease, it doesn’t mean they will be as effective against COVID-19 disease.” Peterson said. “The newer form of the virus is very similar to the earlier SARS-CoV, however, the newer mutations could mean that other non-tested drugs may work better.”

The goal was to find drugs that stick like glue in a special “pocket,” or active site, on the surface of a protein called 3CLpro, which COVID-19 uses to create numerous copies of itself inside infected cells of a patient. The 3CLpro protein is one of many proteins generated inside infected cells, and acts like a scissors to cleave larger proteins into smaller proteins used for constructing new copies of the virus, which then leave the cell to infect other cells. Therefore, researchers are trying to identify drugs that bind to this specific pocket to thwart replication of the virus, so that patient treatment can be improved. The computer analysis required several days of high-performance computing on Amazon’s AWS cloud computing fleet.

Overall, the results indicate that FDA-approved drugs were much less successful in binding to the active site of 3CLpro when compared with investigational and experimental drugs, which are not FDA-approved. The top 5 investigational drugs were Lorecivivint, Tivantinib, Omipalisib, Bictegravir, and Ridinilazole, while the top 5 FDA-approved drugs were Olaparib, Etoposide, Ouabain, Indinavir, and Idelalisib. Bictegravir and Indinavir are both antiviral drugs used for HIV-1 treatment.

Another observation was that the natural supplement Diosmin, which is used without prescription for varicose veins, ranked 22 overall and showed impressive results in terms of its binding strength at the active site. Dr. Peterson said that “before drugs are used for docking into a pocket of a protein, their energy is minimized to a relaxed state, which represents their natural 3-dimensional form as they float around in water inside a cell.” In its energy-minimized state, Diosmin was able to deeply penetrate and fully cover the width of the active site’s pocket better than 99% of the drugs studied. Better yet, it formed 9 hydrogens bonds with 3CLpro, a sign that Diosmin could have a high binding affinity for the active site. Diosmin could therefore potentially serve as a strong inhibitor of the 3CLpro protease of SARS-CoV-2 and could be investigated in human clinical trials. Since a prescription is not required for its use, it could also be formally investigated as a self-medicating natural alternative to synthetic drugs for treating COVID-19. Lastly, the green tea component epigallocatechin gallate, bound to the active site better than 70% of the top 30 antivirals.

Disclaimer: This computational docking study is often the first step in drug research, so the results do not guarantee that Diosmin is an effective inhibitor of 3CLpro. Additional in vitro and in vivo “wet” laboratory testing must be done before confirming the efficacy of Diosmin for treating COVID-19 disease.

To speak with Leif Peterson, Ph.D., contact [email protected] For more information about NXG Logic, LLC, visit www.nxglogic.com

Reference: In Silico Molecular Dynamics Docking of Drugs to the Inhibitory Active Site of SARS-CoV-2 Protease and Their Predicted Toxicology and ADME. DOI: http://dx.doi.org/10.13140/RG.2.2.17657.83045 (April 20, 2020) L.E. Peterson.

NXG Logic, LLC, develops scientific software for machine learning, AI, text mining, and statistical analysis.