<i>In silico</i>
            analysis of the antidepressant fluoxetine and similar drugs as inhibitors of the human protein acid sphingomyelinase: a related SARS-CoV-2 inhibition pathway

Pauletto, Pedro José Tronco; Bortoli, Marco; Omage, Folorunsho Bright; Delgado, Cássia Pereira; Nogara, Pablo Andrei; Orian, Laura; Rocha, João Batista Teixeira da

doi:10.1080/07391102.2022.2148124

Cited by 2 publications

(2 citation statements)

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“…Multiple studies [ 16 , 19 ] have suggested the significance of FIASMAs (functional inhibitors against ASM) for repurposing as potential drugs against COVID-19. One such anti-depressant, namely fluoxetine, has been tested in vitro for the inhibition of ASM [ 20 ]. Various FIASMAs have been identified through in silico, in vitro, or in vivo studies as being potential antiviral drug candidates against SARS-CoV, MERS-CoV, and SARS-CoV-2 [ 6 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

Repurposing FIASMAs against Acid Sphingomyelinase for COVID-19: A Computational Molecular Docking and Dynamic Simulation Approach

et al. 2023

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Over the past few years, COVID-19 has caused widespread suffering worldwide. There is great research potential in this domain and it is also necessary. The main objective of this study was to identify potential inhibitors against acid sphingomyelinase (ASM) in order to prevent coronavirus infection. Experimental studies revealed that SARS-CoV-2 causes activation of the acid sphingomyelinase/ceramide pathway, which in turn facilitates the viral entry into the cells. The objective was to inhibit acid sphingomyelinase activity in order to prevent the cells from SARS-CoV-2 infection. Previous studies have reported functional inhibitors against ASM (FIASMAs). These inhibitors can be exploited to block the entry of SARS-CoV-2 into the cells. To achieve our objective, a drug library containing 257 functional inhibitors of ASM was constructed. Computational molecular docking was applied to dock the library against the target protein (PDB: 5I81). The potential binding site of the target protein was identified through structural alignment with the known binding pocket of a protein with a similar function. AutoDock Vina was used to carry out the docking steps. The docking results were analyzed and the inhibitors were screened based on their binding affinity scores and ADME properties. Among the 257 functional inhibitors, Dutasteride, Cepharanthine, and Zafirlukast presented the lowest binding affinity scores of −9.7, −9.6, and −9.5 kcal/mol, respectively. Furthermore, computational ADME analysis of these results revealed Cepharanthine and Zafirlukast to have non-toxic properties. To further validate these findings, the top two inhibitors in complex with the target protein were subjected to molecular dynamic simulations at 100 ns. The molecular interactions and stability of these compounds revealed that these inhibitors could be a promising tool for inhibiting SARS-CoV-2 infection.

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Section: Introductionmentioning

confidence: 99%

Repurposing FIASMAs against Acid Sphingomyelinase for COVID-19: A Computational Molecular Docking and Dynamic Simulation Approach

et al. 2023

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“…In fact, a series of compounds known by the acronym FIASMAs have been described to release ASM into the lysosomal lumen, which is then followed by its proteolytic degradation. 19,23 The molecular interactions that are disrupted by FIASMAs involve the breakdown of the electrostatic and hydrophobic interactions that stabilize the close contact of the enzyme with the components of the internal half of the lysosomal bilayer membrane 24 (Figure 4).…”

Section: Fiasmasmentioning

confidence: 99%

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

Pauletto

Delgado

Rocha

2023

Cell Biochemistry & Function

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In the last 2 years, different pharmacological agents have been indicated as potential inhibitors of SARS-CoV-2 in vitro. Specifically, drugs termed as functional inhibitors of acid sphingomyelinase (FIASMAs) have proved to inhibit the SARS-CoV-2 replication using different types of cells. Those therapeutic agents share several chemical structure characteristics and some well-known representatives are fluoxetine, escitalopram, fluvoxamine, and others. Most of the FIASMAs are primarily used as effective therapeutic agents to treat different pathologies, therefore, they are natural drug candidates for repositioning strategy. In this review, we summarize the two main proposed mechanisms mediating acid sphingomyelinase (ASM) inhibition and how they can explain the inhibition of SARS-CoV-2 replication by FIASMAs. The first mechanism implies a disruption in the lysosomal pH fall as the endosome-lysosome moves toward the interior of the cell. In fact, changes in cholesterol levels in endosome-lysosome membranes, which are associated with ASM inhibition is thought to be mediated by lysosomal proton pump (ATP-ase) inactivation. The second mechanism involves the formation of an extracellular ceramide-rich domain, which is blocked by FIASMAs. The ceramide-rich domains are believed to facilitate the SARS-CoV-2 entrance into the host cells.

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In silico analysis of the antidepressant fluoxetine and similar drugs as inhibitors of the human protein acid sphingomyelinase: a related SARS-CoV-2 inhibition pathway

Cited by 2 publications

References 51 publications

Repurposing FIASMAs against Acid Sphingomyelinase for COVID-19: A Computational Molecular Docking and Dynamic Simulation Approach

Repurposing FIASMAs against Acid Sphingomyelinase for COVID-19: A Computational Molecular Docking and Dynamic Simulation Approach

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

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