A team of chemists from HSE University and the Zelinsky Institute of Organic Chemistry used molecular modeling to find out that two medications that have been known for a long time can be used to fight SARS-CoV-2. These are disulfiram, which is used to treat alcoholism, and neratinib, an experimental drug being used to treat breast cancer. The paper about the discovery has been available online since August 4, 2020, in the 4th issue of Mendeleev Communications journal.
The structural elements of the virus that are less subject to mutation during its evolution should be chosen as a target for the potential treatment. Otherwise, a medication effective against one strain would no longer be effective against another. The best candidates for this are conservative proteins, such as the SARS-CoV-2 virus main protease M pro. In addition to being resistant to mutations, M pro plays a major role in coronavirus replication, which means that its inhibition (blocking its function) is able to slow down or even completely stop its reproduction inside the body.
Usually, the process of docking, as with a port dock and a ship entering it, is used for molecular modelling in simple cases. Two molecules participate in docking. One is called a ‘ligand’ (here, it is a medicine), and the other one is ‘receptor’ (or active site) of the target protein, such as Mpro, which can be used to ‘dock’. An effective drug docks with the active site, by covalent links, which makes the enzyme dysfunctional or destroys it. But classical docking does not work in SARS-CoV-2.
To overcome this problem, chemists from HSE University and the Zelinsky Institute decided to use ‘on-top docking’, which they came up with shortly before the pandemic.
We decided not to focus on the previously described active site, but to investigate the whole surface of M pro protein with many medications, hoping that the big calculation powers would return useful dockings.”
The ers used the SARS-CoV-2 Mpro space style created in January 2020 from the PDB database (ID 6LU7). Possible drugs have been extracted from the U.S. Food and Drug Administration (FDA) approved drug database. The team’s own algorithms were used to design.
Knowledge of the models has shown that sulfur-containing drugs have exceptionally superior ligand efficacy at the active center of sarS-CoV-2’s main Mpro protease, although I disulfirame four important solid interactions.
Today, it is most commonly used for treating alcoholism. Disulfiram fights SARS-CoV-2 in two ways. First, as previously demonstrated in vitro with SARS and MERS coronaviruses, it is a covalent inhibitor. In addition, it fights COVID-19 symptoms such as the significant decrease in reduced glutathione, which is an important antioxidant. This deficiency may lead to severe manifestations of the disease.
In addition to disulfiram, the Russian chemists were the first to predict the potential efficiency of neratinib, an irreversible tyrosine kinase inhibitor, against SARS-CoV-2. Just recently, in 2017, FDA approved neratinib as an adjuvant treatment of breast cancer.
Modeling has shown that both potential inhibitors of the main coronavirus protease (M pro) are, presumably, covalent. For example, disulfiram can probably block the M pro enzymatic activity by thiol-disulfide exchange reaction, while neratinib binding suggests the possibility of covalent interaction similarly to covalent peptide inhibitors.
Tests conducted on July 27, 2020 at Reaction Biology Corp., a qualified laboratory in the United States, showed that disulfiirame inhibits M pro at a concentration of one hundred nm, showing the results of the modeling. Unfortunately, at the time the substance – neratinib – showed activity in M pro, however, it was inadequate for clinical use.
Meanwhile, the biggest achievement is the demonstration that the “tie at the top” technique works and provides realistic and controllable results. The team’s plans for the end of 2020 and 2021 come with molecular models of disease remedies that have proven to be destructive but have not yet spread around the world.
National Research University Graduate School of Economics
Stroylov, V.S. – Svitanko, I.V (2020) Computer identity of disulfiirame and neratinib as purported SARS-CoV-2 protease inhibitors. Mendeleev Communications. doi.org/10.1016/j.mencom.2020.07.004.
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