In Silico Analysis of the Antidepressant Fluoxetine and Related Drugs at SARS-CoV-2 Main Protease (Mpro) and Papain-like Protease (PLpro)

Abstract

Background: SARS-CoV-2 main protease (Mpro or 3CLpro) and papain-like protease (PLpro) are common viral targets for repurposed drugs to combat COVID-19 disease. Recently, several anti-depressants (such as fluoxetine, venlafaxine and citalopram) belonging to the Selective Serotonin Reuptake Inhibitors (SSRIs) and the Serotonin-Norepinephrine Reuptake Inhibitors (SNRI) classes have been shown to in vitro inhibit viral replication. Aim: Investigate a possible action of fluoxetine and derivatives on SARS-CoV-2 protease sites. Methods: molecular docking was performed using AutoDock Vina. Both proteases structures and different drugs conformations were used to explore the possibility of SARS-CoV-2 inhibition on a Mpro or PLpro related pathway. Drug structures were obtained by optimization with the Avogadro software and MOPAC using PM6 method. Results were analysed on Discovery Studio Visualizer. Results: The results indicated that Mpro interacted in a thermodynamically favorable way with fluoxetine, venlafaxine, citalopram, atomoxetine, nisoxetine and norfluoxetine in the region of the active site, whether PLpro conformers did not come close to active site. Conclusion: In an in silico perspective, it is likely that the SSRIs and other anti-depressants could interact with Mpro and cause the enzyme to malfunction. Unfortunately, the same drugs did not present similar results on PLpro crystal, therefore no inhibition is expected on an in vitro trial. Anyway, in vitro test are necessary for the better understanding the links between SARS-CoV-2 proteases and anti-depressants.

Acid sphingomyelinase (ASM) and COVID‐19: A review of the potential use of ASM inhibitors against SARS‐CoV‐2

“…In addition to their specific therapeutic effects, the FIASMAs can have potential broad cellular and molecular effects, for instance, as cytoprotective, and anti‐inflammatory agents 19 . Of potential therapeutic importance in terms of drug repurposing, various FIASMAs have also been tested as antibacterial and antiviral agents experimentally 9,10,12,27,28 and several other currently used molecules for the treatment of different diseases. For example, fluoxetine and escitalopram are two well‐known antidepressants and have been described as FIASMAs 10,19,20 …”