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.
Pedro José Tronco PaulettoMarco BortoliFolorunsho Bright OmageCássia Pereira DelgadoPablo Andrei NogaraLaura OrianJoão Batista Teixeira RochaPublished in: Journal of biomolecular structure & dynamics (2022)
Acid Sphingomyelinase (ASM) is a human phosphodiesterase that catalyzes the metabolism of sphingomyelin (SM) to ceramide and phosphocholine. ASM is involved in the plasma membrane cell repair and is associated with the lysosomal inner lipid membrane by nonbonding interactions. The disruption of those interaction would result in ASM release into the lysosomal lumen and consequent degradation of its structure. Furthermore, SARS-CoV-2 infection has been linked with ASM activation and with a ceramide domain formation in the outer leaflet of the plasma membrane that is thought to be crucial for the viral particles recognition by the host cells. In this study, we have explored in silico the behavior of fluoxetine and related drugs as potential inhibitors of ASM. Theoretically, these drugs would be able to overpass lysosomal membrane and reach the interactions that sustain ASM structure, breaking them and inhibiting the ASM. The analyses of docking data indicated that fluoxetine allocated mainly in the N-terminal saposin domain via nonbonding interactions, mostly of hydrophobic nature. Similar results were obtained for venlafaxine, citalopram, atomoxetine, nisoxetine and fluoxetine's main metabolite norfluoxetine. In conclusion, it was observed that the saposin allocation may be a good indicative of the drugs inhibition mechanism, once this domain is responsible for the binding of ASM to lysosomal membrane and some of those drugs have previously been reported to inhibit the phosphodiesterase by releasing its structure in the lysosomal lumen. Our MD data also provides some insight about natural ligand C18 sphingomyelin conformations on saposin.Communicated by Ramaswamy H. Sarma.
Keyphrases
- sars cov
- endothelial cells
- molecular docking
- induced apoptosis
- drug induced
- molecular dynamics
- heart failure
- respiratory syndrome coronavirus
- ultrasound guided
- protein protein
- signaling pathway
- small molecule
- machine learning
- cell proliferation
- major depressive disorder
- deep learning
- fatty acid
- cell therapy
- aortic valve
- molecular dynamics simulations
- endoplasmic reticulum stress
- cell cycle arrest
- data analysis
- dna binding
- working memory