Background: Sphingosine kinase 1 (SK1) overexpression and elevated sphingosine-1-phosphate (S1P)
levels have been correlated with many disease states from cancer to inflammatory diseases to diabetes. Even though
SK1 inhibitors are of consideberable interest as effective chemotherapeutic agents, poor potency, lack of selectivity
and poor pharmacokinetic properties have been major problems in the first generation SK1 inhibitors.
Objective: There is an urgent need for the discovery of novel in vivo, stable selective SK1 inhibitors with improved
potency. The primary object of this study was to identify potential novel leads for orthosteric inhibition of SK1.
Methods: We propose a series of compounds from different chemotypes as potential selective SK1 inhibitors via virtual
screening of the ZINC database using ligand-based and structure-based pharmacophore models, molecular docking,
substructure search, selectivity calculations. Molecular dynamics (MD) simulations revealed key insights into the
binding mode and the stability of the SK1-ligand complex.
Results: Ten ligands were proposed as potential SK1 inhibitors based on the high induced fit docking scores, BEI,
LLE and %HOA. Ligands 2, 3, 5 and 9 were found to be selective toward SK1 with favorable binding free energy of -
95 ± 5 kcal/mol. MD simulation of ligand 5 showed that the ligand-SK1 complex reached equilibrium with favorable
hydrogen bonding and hydrophobic interactions. The four selective compounds have less than 0.24 similarity with
previously discovered potent inhibitors.
Conclusion: The proposed compounds may serve as potential novel leads for orthosteric inhibition of SK1.