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USP identifies drugs with potential against SARS-CoV-2

Publicado em 02 setembro 2021

Using a technique known as drug repositioning, researchers at the Institute of Biomedical Sciences at the University of São Paulo (ICB-USP) have found seven possible drugs to inhibit the replication of the new coronavirus. The products are already approved by the Food and Drug Administration (FDA, regulatory agency of the United States), which would facilitate the advancement to clinical trials if their effectiveness is proven in vitro, in tests performed with cell lines.

The results of the research – supported by FAPESP through three projects – were published in the Journal of Biomolecular Structure and Dynamics.

The investigation focused on the SARS-CoV-2 enzyme 3CLpro, considered essential for virus replication. Using machine learning techniques, the scientists tested more than 11,000 molecules and selected those that showed greater affinity with the target molecule, as well as greater stability within the active site – the region of the protein where the chemical reaction takes place.

“These computational predictions we made elect seven molecules that could be promising for testing in cells. If they work in vitro, we can see them being tested on humans. The advantage of testing medicines that already exist on the market is that the effects of toxicity and side effects are already widely known”, emphasizes Cristiane Guzzo, coordinator of the study.

“Therefore, after validation in trials in vitro, it would be possible to carry out clinical trials in patients with covid-19.”

The finding may also be important in establishing the criteria and properties that the drug must have to inhibit the 3CLpro enzyme. “We saw that the best compounds are those that interact favorably with five specific amino acid residues of the enzyme. Therefore, these residues can be used to discover other inhibitors”, explains postdoctoral fellow Anacleto Silva de Souza, first author of the article.

Enzyme Actuation

Coronavirus 3CLpro is a protease responsible for breaking a chain of viral proteins (polyprotein) into its functional subunits, thus allowing RNA replication and assembly of new viral particles that will infect other cells. The hypothesis is that, by inhibiting 3CLpro, it cannot perform its function and the virus stops replicating and proliferating, reducing the viral load and the severity of the disease.

This is a different target from other studies, many of them focused on protein spike, which lies on the surface of the virus and is responsible for interacting with the host cell. “We chose 3CLpro because there was already a considerable amount of information about it, due to more than 15 years of research with SARS-CoV’s 3CLpro [coronavírus que causou a epidemia de síndrome respiratória aguda grave entre 2002 e 2003]”, says Guzzo.


To simulate the interaction of drugs with the protease, the researchers developed three mathematical models, using artificial neural networks and two regression models. These quantitative models, known as QSAR, were based on information from the literature on molecules that were already known to have inhibitory properties against the 3CLpro enzyme.

With the QSAR models, an affinity prediction of 11,000 molecules was made using the Drugbank database, a repository that combines detailed chemical and pharmacological data on approximately 4,300 drugs. Based on the computational results, 2,500 molecules were discarded for having low affinity with the enzyme. Of the 8,500 compounds that followed, 14 molecules with different pharmacological properties (drugs for the treatment of migraine, respiratory diseases, antimicrobial action and natural products) were selected for computational simulation between these drugs and the enzyme.

“To inhibit the enzyme, it is not enough just predicted high affinity, it is necessary for the molecule to be able to remain bound to the target. Otherwise, the enzyme’s function is reactivated. So we simulated how these 14 molecules would behave within the active site of 3CLpro. We carry out a docking [acoplamento entre moléculas] followed by molecular dynamics to check whether the compound is stable within the enzyme, and that leaves seven candidates,” the researchers explain.

Scientists now intend to confirm these predictions in biochemical experiments, through cloning of 3CLpro. If the discovery is validated, the expectation is to establish partnerships with other ICB laboratories to test the drugs in vitro.