Identificación y modelamiento de mutaciones que otorgan resistencia a inhibidores de la enzima proteasa Mpro del virus SARS-CoV2

Abstract

In January 2020, an outbreak of a new Coronavirus (CoV-2) was reported, which causes Acute Respiratory Syndrome (SARS). SARS-CoV-2 now does not have therapeutic options that prevent or stop the viral infection. One of the targets for developing drugs against this virus is its main protease, Mpro. The compounds Carmofur and N3 have been shown to exhibit potent Mpro inhibitory activity. However, the SARS-CoV-2 genome mutates rapidly. The present work proposes the modeling of the structures of point mutations in the main protease of SARS-COV-2 and the analysis of the implications that these would have on the interaction with Carmofur and N3. A multiple alignment of the viral proteins homologous to Mpro suggests that the structure of the Mpro protease of SARS-CoV-2 could undergo modifications in the amino acids of the active site. The possible mutations identified were modeled in Wincoot and refined in YASARA. The analysis of possible variations in the binding properties of Carmofur and N3 to Mpro was carried out by molecular coupling. The results show that point mutations in the active site of Mpro can modify the mode of binding of these inhibitors to the enzyme, giving rise to the appearance of resistance. These results are of great relevance, since they allow us to anticipate the effect of different mutations in the way in which potential Mpro inhibitors act and thus design new inhibitors that can overcome the effect of resistance to these drugs.