Virtual screening based on molecular docking of lysosomotropic compounds as therapeutic agents for COVID-19

Abstract

INTRODUCTION: COVID-19 has quickly become one of the main pathogens of the human respiratory tract and poses a great threat to public health. The high number of cases has caused the World Health Organization to declare a global state of emergency. In addition, due to the limited number of therapeutic strategies, high levels of mortality have been observed in several regions of the world. Within this context, repositioning of drugs based on lysosomotropic and endolysosomal pH modulating effects can provide additional options for therapy and prevention of the new disease. METHODS: Molecular docking analyses of these lysosomotropic agents were performed, namely of fluoxetine, imipramine, chloroquine, verapamil, tamoxifen, amitriptyline and chlorpromazine against important targets for the pathogenesis of SARS-CoV-2. RESULTS: The results revealed that the inhibitors bind to distinct regions of Mpro COVID-19, with variations in RMSD values from 1.325 to 1.962 Å and a binding free energy of -5.2 to -4.3 kcal/mol. Furthermore, the analysis of the second target showed that all inhibitors bonded at the same site as the enzyme and the interaction resulted in an RMSD variation of 0.735 to 1.562 Å and binding free energy ranging from -6.0 to -8.7 kcal/mol. CONCLUSION: Therefore, this study allows proposing the use of these lysosomotropic compounds. However, these computer simulations are just an initial step toward conceiving new projects for the development of antiviral molecules.

Keywords: COVID-19; Inhibitors; lysossomotropics; molecular docking