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Computational prediction of potential inhibitors for SARS-COV-2 main protease based on machine learning, docking, MM-PBSA calculations, and metadynamics

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  • Isabela de Souza Gomes
  • Charles Abreu Santana
  • Leandro Soriano Marcolino
  • Leonardo Henrique França de Lima
  • Raquel Cardoso de Melo-Minardi
  • Roberto Sousa Dias
  • Sérgio Oliveira de Paula
  • Sabrina de Azevedo Silveira
  • Alessio Lodola (Editor)
Article numbere0267471
<mark>Journal publication date</mark>22/04/2022
<mark>Journal</mark>PLoS ONE
Issue number4
Number of pages20
Publication StatusPublished
<mark>Original language</mark>English


The development of new drugs is a very complex and time-consuming process, and for this reason, researchers have been resorting heavily to drug repurposing techniques as an alternative for the treatment of various diseases. This approach is especially interesting when it comes to emerging diseases with high rates of infection, because the lack of a quickly cure brings many human losses until the mitigation of the epidemic, as is the case of COVID-19. In this work, we combine an in-house developed machine learning strategy with docking, MM-PBSA calculations, and metadynamics to detect potential inhibitors for SARS-COV-2 main protease among FDA approved compounds. To assess the ability of our machine learning strategy to retrieve potential compounds we calculated the Enrichment Factor of compound datasets for three well known protein targets: HIV-1 reverse transcriptase (PDB 4B3P), 5-HT2A serotonin receptor (PDB 6A94), and H1 histamine receptor (PDB 3RZE). The Enrichment Factor for each target was, respectively, 102.5, 12.4, 10.6, which are considered significant values. Regarding the identification of molecules that can potentially inhibit the main protease of SARS-COV-2, compounds output by the machine learning step went through a docking experiment against SARS-COV-2 Mpro. The best scored poses were the input for MM-PBSA calculations and metadynamics using CHARMM and AMBER force fields to predict the binding energy for each complex. Our work points out six molecules, highlighting the strong interaction obtained for Mpro-mirabegron complex. Among these six, to the best of our knowledge, ambenonium has not yet been described in the literature as a candidate inhibitor for the SARS-COV-2 main protease in its active pocket.