In silico drug repurposing of anticancer drug 5-FU and analogues against SARS-CoV-2 main protease: molecular docking, pharmacokinetics and chemical reactivity

Abstract

Since the last COVID-19 outbreak, several approaches have been put forward to quickly tackle this global calamity. One of the strategies employed by a handful of researchers is the so-called drug repurposing, which consists in finding new therapeutic uses for approved drugs. Following the same paradigm, we report in the present study an investigation of the potential inhibitory activity of 5-FU and nineteen of its analogues against the SARS-CoV-2 main protease in the framework of molecular docking. This work also discusses the profile of druggability of the best binding candidates as well as their inherent reactivity using ADMET and quantum mechanics methods respectively. From the calculations performed, four candidates show promising results with respect to the binding affinity to the target protease, 3CLpro, the therapeutic profile of druggability and safety. Molecular electrostatic potential, Fukui functions and frontier molecular orbitals are scrutinized to discuss the global and local reactivity of these candidates. Further in-vitro and in-vivo investigations are needed to shed light on the possible mechanism of pharmacological action of the proposed ligands.