University of São Paulo: USP scientists identify seven drugs with potential against covid-19

Through a technique called drug repositioning, researchers at the Institute of Biomedical Sciences (ICB) at USP found seven possible drugs to inhibit the replication of the coronavirus. The drugs, tested in computer simulations, are already approved by the Food and Drug Administration (FDA), a regulatory body in the United States, which would facilitate the advancement to clinical tests if their effectiveness is proven in vitro (in laboratory tests). The work was published in an article in the journal Journal of Biomolecular Structure and Dynamics in August.

Using machine learning, the scientists tested more than 11,000 molecules and selected those that obtained greater affinity with the enzyme 3-chemotrypsin-like protease (3CLpro), the target of the study, and that registered greater stability within the active site (region where it occurs chemical reaction) of this protein. 3CLpro is the main protease of sars-cov-2 and is essential for the virus to be able to replicate.

“These computational predictions we made selected seven molecules that could be promising in cell tests. If they work in vitro , we can see them being tested in 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”, highlights professor Cristiane Guzzo, coordinator of the study. “Therefore, after validation in in vitro assays , it would be possible to carry out clinical tests in patients with covid-19.”

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

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The coronavirus 3CLpro enzyme is a protease responsible for breaking a chain of viral proteins (polyprotein) into its functional subunits, and allowing viral 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 dose and the severity of the disease.

This is a different target from other studies, which usually focus on the Spike protein, which is on the surface of the virus and is responsible for its interaction with the receptor cell, thus allowing the start of the viral infection process. “We chose 3CLpro because there was already a considerable amount of information about it, due to more than 15 years of research with 3CLpro by sars-cov, referring to the 2002-2003 epidemic”, details Cristiane.

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. 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 to have the predicted high affinity, it is necessary for the molecule to be able to remain attached to it. If not, the enzyme function is reactivated”, explains the professor. The researchers simulated how these 14 molecules would behave within the active site of 3CLpro and, after testing, seven candidates remained. Scientists will now work 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 .

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