Identification of Potential SPHK1 Inhibitors Based on Structural Optimization by Molecular Simulation

Sphingosine Kinase 1 (SPHK1) is overexpressed in various types of human cancers, regulating many important cellular processes during tumorigenesis. Targeting SPHK1 may provide new strategies for treating tumors. Here, the structure-activity relationship was studied by using CoMFA and CoMSIA models. Experimental results showed that CoMFA (q2=0.621; n=10; r2=0.992) and CoMSIA (q2=0.585; n=7; r2=0.967) have suitable predictability. The structure-activity relationship of the compounds was analyzed by the counter maps of the steric, electrostatic, hydrophobic, and hydrogen bond receptor fields. Subsequently, the compounds were docked with SPHK1 using the Surfex-Dock method to explore their interactions. The results show that the binding between SPHK1 and the inhibitors is mainly dependent on van der Waal, Carbon Hydrogen Bond and hydrophobic interaction. Furthermore, the potential activities and ADME/T properties of 6 newly designed compounds were predicted through 3D-QSAR models and online tools. The newly designed compounds were validated to have better activities and suitable ADME/T properties. In addition, Molecular Dynamics (MD) simulation showed that some key residues play significant role in the active site, including Ala339, Ala170, Ala115, Asp81, Gly342, Phe288 Ser164, Phe188, Ile170, etc. This study may help to discovery and design novel SPHK1 inhibitors.