RESUMO
The signaling of sphingosine kinase 1 (SphK1) and sphingosine-1-phosphate (S1P) regulates various diseases, including multiple sclerosis, atherosclerosis, rheumatoid arthritis, inflammation-related ailments, diabetes, and cancer. SphK1 is considered an attractive potential drug target and is extensively explored in cancer and other inflammatory diseases. In this study, we have investigated the inhibitory potential and binding affinity of SphK1 with cholic acid (CA), syringic acid (SA), and mangiferin (MF) using a combination of docking and molecular dynamics (MD) simulation studies followed by experimental measurements of binding affinity and enzyme inhibition assays. We observed these compounds bind to SphK1 with a significantly high affinity and eventually inhibit its kinase activity with IC50 values of 28.23 µM, 33.35 µM, and 57.2 µM for CA, SA, and MF, respectively. Further, the docking and 100 ns MD simulation studies showed that CA, SA, and MF bind with the active site residues of SphK1 with favorable energy and strong non-covalent interactions that might be accountable for inhibiting its kinase activity. Our finding indicates that CA, SA, and MF may be implicated in designing novel anti-cancer therapeutics with an improved affinity and lesser side effects by targeting SphK1.