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

Abstract

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.

Medications Modulating the Acid Sphingomyelinase/Ceramide System and 28-Day Mortality among Patients with SARS-CoV-2: An Observational Study

“…These results confirm and extend the preclinical [ 13 , 15 , 16 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 36 , 37 ], computational molecular docking [ 38 ], observational [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 39 ], and clinical [ 40 , 41 , 42 , 43 , 44 , 45 ] study findings suggesting that the ASM/ceramide system may play an important role in SARS-CoV-2 infection, particularly in the case of the FIASMA medications fluoxetine [ 17 , 46 , 47 ], escitalopram [ 27 , 29 ], and amlodipine [ 32 , 48 ]. These findings are also in line with studies indicating that clinical severity and inflammation markers in patients with COVID-19 are significantly associated with sphingomyelinase and ceramidase activity and the plasma levels of ceramides [ 3 , 4 , 5 , 17 , 49 , 50 , 51 ].…”

Pharmacoinformatics-Based Approach for Uncovering the Quorum-Quenching Activity of Phytocompounds against the Oral Pathogen, Streptococcus mutans

“…In silico and in vitro agonistic activity of ligands have been studied for the treatment of diabetes [ 44 , 45 ], Parkinson’s disease [ 46 ], and cardiac diseases [ 47 ]. The antagonistic activity of ligands against S. mutans [ 48 , 49 ], Leishmania donovani [ 50 ], Helicobacter pylori [ 51 ], and SARS-CoV-2 [ 52 ] has also been studied. All these research works corroborate the necessity of in vitro experiments in the validation of computational analysis.…”

The Sphingolipid-Signaling Pathway as a Modulator of Infection by SARS-CoV-2

“…Through computational molecular docking and dynamic simulation approaches, identification of potential ASM inhibitors was performed; hence, Dutasteride, Cepharanthine, and Zafirlukast were recently identified with the lowest binding affinity scores (−9.7, −9.6, and −9.5 kcal/mol, respectively). Furthermore, computational ADME analysis highlighted the non-toxic properties of Cepharanthine and Zafirlukast, thus suggesting these inhibitors as potential promising tools for the inhibition of SARS-CoV-2 infection [95]. Indeed, these drugs have been shown to lower Cer concentration, hindering SARS-CoV-2 entry into cells and reducing hyperinflammation and pro-inflammatory cytokines (e.g., IL-6), which are considered risk factors for severe disease progression (such as hypertension, obesity, and thromboembolic complications), as well as the incidence of intubation and mortality in COVID-19 [96,97].…”