New computational method speeds up the search for drugs for covid-19 – 11/27/2021

A study conducted by researchers from Brazil, Germany and Finland proposes a new standard for simulations, using computational techniques, which promises to accelerate the search for bioactive compounds against the virus that causes covid-19. The procedure was applied in the study of one of the main proteins acting in the reproductive cycle of Sars-CoV-2, which has received great attention from scientists and the pharmaceutical industry for being considered a target for antiviral drugs. The researchers estimate that the method they developed could reduce the time spent in the initial phase of basic research, which lasts from two to three years, to less than a year.

As the authors explain, Sars-CoV-2 has an outer layer of proteins full of the amino acid cysteine, which needs to be intact and active for the virus to maintain its activity. The main protease, an enzyme that breaks the peptide bonds between amino acids and proteins, is Mpro (acronym derived from the term in English main protease), responsible for cleaving polyproteins (protein chains) into smaller proteins. These, in turn, are related to the production of RNA that encodes structural proteins of the pathogen, such as spike (which binds to the human cell receptor, enabling the infection) and those that form the viral envelope (outer layer that protects the genetic material).

Researchers and the drug industry look to Mpro as a target for drug development against covid-19 because the possibility of influencing or blocking this cleavage represents a break in one of the early stages of the virus’s reproduction cycle. One of the ways is the synthesis of chemical components designed to bind to specific points on the protein, in order to block this process and inactivate it.

The pharmaceutical industry takes, on average, 20 years to develop new drugs. One of the results of the study published in the Journal of Biomolecular Structure and Dynamics was the construction of a standard for simulations that can reduce the search time for new bioactive compounds against Sars-CoV-2 to less than a year. The search for the active compound is made right at the beginning of the drug’s development, a phase that normally takes two to three years

“To produce the vaccines, information already reported from Sars-CoV-1 was used, of which Sars-CoV-2 is an evolution, accelerating the pre-clinical phase. We cannot do the same in basic research to develop medicines, because we cannot we have the necessary background information for that”, explains Glaucio Monteiro Ferreira, from the Department of Clinical and Toxicological Analyzes, Faculty of Pharmaceutical Sciences, University of São Paulo (FCF-USP) and the main author of the article. He conducted part of the research at the Department of Oncology and Pneumonology, Internal Medicine VIII at the University Hospital of Tübingen, Germany, with support from FAPESP (16/12899-6 and 19/24112-9).

Another factor that demands more time for research and development of a new drug are studies on how it will be made available – whether orally, as a pill or liquid, or in an injectable form, for example. “If it’s a drug to be ingested, we need to ensure that it goes through all the barriers of the human body to get where it has to do the action. These are details that require more time to develop a drug compared to a vaccine,” he adds.

Unpublished data

Using a combination of tools such as bioinformatics and structural biology, Ferreira investigated Mpro (also called 3CLpro) – one of the viral proteins that need to have the amino acid cysteine ​​as a substrate or “food” to fulfill its function.

Several previous studies show that there are proteins that function in the monomeric state, those that have only one protein chain. “But we knew that Sars-CoV-1 has a duplicated protein chain, they are dimers. This complicates the search for a drug, as we need to find a compound that can prevent the double chain from forming”, he says.

A previous study for Sars-CoV-1 had already reached promising results, using covalent inhibitors linked to cysteine ​​- that is, a compound that bound more “strongly” to this amino acid. The intention of this study was to find a way to prevent the cysteine ​​from being available for the protein to “feed” on it, inhibiting its action.

Sars-CoV-2 is also a dimer. In order to start the search for a compound that could interfere in the formation of the two chains, simulations come into play. Using molecular dynamics, a computer simulation method that studies the physical movement of atoms and molecules, a virus attack on a human cell was simulated.

Ferreira’s team of scientists began carrying out simulations in which the protein had one and two ligands. So they found that research focused on analyzing single-chain proteins used an experiment, X-ray diffraction, which captured results after the protein had consumed the cysteine ​​and separated. As a result, they were unable to focus on the process of interest, the blocking of this phase in protein replication.

As a way to apply the simulation to study the potential of new drugs to fight the covid-19 virus, two inhibitors were used, N1 and N3, which affect the action of the Mpro protein. The researchers found that the first is more effective, not allowing the donation of electrical charge to cysteine, that is, blocking the “feeding” of the protein.

“With the simulations we did, we arrived more quickly at this inhibitor, which can really kill the enzyme. Our simulations indicate the potential of this compound to be a much more potent drug and to be much closer to becoming a drug”, he points out. Coincidentally, Pfizer recently released an initiative to find a drug for SARS-CoV-2 that targets, precisely, an inhibitor of the Mpro protein, which occurred long after Ferreira’s research began.

The Brazilian researcher worked together with Thales Kronenbergerb and Antti Poso, who work at the Department of Oncology and Pneumonology, Internal Medicine VIII, University Hospital of Tübingen, Germany, and at the School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland , in Finland; Arun Kumar Tonduruc, from the same department at the University of Tübingen; Rosario Dominguez Crespo Hirata and Mario Hiroyuki Hirata, both from the Department of Clinical and Toxicological Analysis of the Faculty of Pharmaceutical Sciences at USP. The research was carried out during Ferreira’s post-doctoral studies, at the Laboratory of Molecular Biology Applied to Diagnosis and Pharmacogenomics (LBMAD), under the supervision of Professor Hirata.

All sign the article SARS-COV-2 Mpro conformational changes induced by covalently bound ligands, which can be read at:

This text was originally published by Agência FAPESP under the Creative Commons CC-BY-NC-ND license. Read the original here.

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