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Identification of inhibitors of the RdRp and Mpro enzymes of SARS-CoV-2 virus by structural homology

Abstract:

TCOVID-19 has enormously impacted global public health due to the high infection and mortality rates associated with the SARS-CoV-2 virus-causing disease. The World Health Organization (WHO) approved 10 safe and effective vaccines. However, there are still significant limitations to their administration in developing countries and remote locations. Concerns remain about the emergence of virus variants that may evade immunity acquired through vaccination. In addition to preventing infection, effective therapeutic agents are needed to treat patients diagnosed with COVID-19. Under this context, the present study aimed to perform a structure-based virtual screening of the protease (Mpro) and RNA-dependent RNA polymerase (RdRp) enzymes of SARS-CoV-2. For this purpose, homologous protein inhibitors belonging to different viruses were tested. Multiple sequence alignment of these enzymes allowed us to recognize the high conservation of these enzymes between species, especially of the regions comprising the inhibitor binding sites. Therefore, it follows that it is possible to employ a bkp_redirection approach to inhibitors that were designed to treat other viral diseases. Molecular docking experiments identified that RTP inhibitors (binding affinity = -7.3 kcal/mol) and V3D (binding affinity = -8.0 kcal/mol) are excellent inhibitors of RdRp and Mpro, respectively. These results suggest that these molecules can virtually bind and inhibit the activity of RdRp and Mpro and thus constitute potential drugs to combat SARS-CoV-2.