Identification of Synthetic 2-Mercaptobenzimidazole Derivatives as Inhibitors of Spike Protein of SARS-CoV-2 by Virtual Screening

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spread worldwide and caused the COVID-19 pandemic. Despite countless efforts in searching for repositioned drugs to treat this disease, the results are still modest. Thus, searching for new compounds as promising drugs to treat this disease is crucial. 2-Mercaptobenzimidazole, a scaffold found in many biologically relevant compounds, has been extensively studied due to its range of biological activities. Using in silico tools, this study aimed to identify 2-mercaptobenzimidazole derivatives as potential drugs to inhibit SARS-CoV-2 infection by blocking spike protein – human angiotensin-converting (hACE2) enzyme interaction. 61 compounds were screened to evaluate their absorption, distribution, metabolism, and excretion (ADME) properties. The compounds that did not violate any Lipinski or Veber rules were subjected to molecular docking interactions to verify their ability to inhibit spike glycoprotein from binding to the hACE2 enzyme. The docking scores for these compounds were superior to the antiviral drugs Remdesivir and Umifenovir, proven to be potential drugs against COVID-19. Furthermore, 2-mercaptobenzimidazole derivatives have been shown to interfere in amino acids involved in key contact sites between SARS-CoV-2-CTD and hACE2 subdomain I. Finally, some toxicological properties were predicted, and the compounds exhibited few (or none) alerts for toxic endpoints as well as low predicted acute oral toxicity (LD50). In this way, the results presented in this work should contribute to discovering new drugs against SARS-CoV-2.