Abstract
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
Keywords:
Acknowledgement
The authors would like to thank the financial support by CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico) and Coordination for Improvement of Higher Education Personnel CAPES/PROEX (n° 23038.005848/2018-31; n°0737/2018). P.J.T.P. was supported by PIBIC, F.B.O., J.B.T.R., C.P.D., and P.A.N., were funded by CAPES (Edital 88887.354370/2019-00, 88887.512885/2020-00, and 88887.511828/2020-00). M.B. and L.O. acknowledge the C3P high performance computing facility of the Department of Chemical Sciences of the University of Padova (Padova, Italy) and the CNAF center of the Italian institute of Nuclear Physics (INFN, Bologna, Italy) for the computational infrastructure (project Insight on Nitrogen Chalcogen Interaction, INCIpit, p. i.: M.B.). F.B.O., P. A. N., J. B. T. and L. O. acknowledge the CINECA consortium (Bologna, Italy) for the access to the computational infrastructures (ISCRA C project HP10CAQKAM PROSIT2 (SARS-CoV-2 Proteases: Selenium based Inhibitors 2), p. i.: L. O.).
Disclosure statement
The authors declare no conflicts of interest.