Sphingosine kinase 1 (SK1) allosteric inhibitors that target the dimerization site. (August 2017) - Bayraktar, Ozge
Graphical abstract: Highlights: A novel SK1 dimer structure is proposed based on template-based modeling. Two potential allosteric sites are determined on the dimer interface. 22 novel ligands are potential allosteric SK1 inhibitors. Five ligands are specific to SK1 and the allosteric sites. MD simulations verify the dimer model and the stability of SK1-ligand complexes. Abstract: The sphingosine kinase 1 (SK1)/sphingosine-1-phosphate (S1P) signaling pathway is a crucial target for numerous human diseases from cancer to cardiovascular diseases. However, available SK1 inhibitors that target the active site suffer from poor potency, selectivity and pharmacokinetic properties. The selectivity issue of the kinases, which share a highly-conserved ATP-pocket, can be overcome by targeting the less-conserved allosteric sites. SK1 is known to function minimally as a dimer; however, the crystal structure of the SK1 dimer has not been determined. In this study, a template-based algorithm implemented in PRISM was used to predict the SK1 dimer structure and then the possible allosteric sites at the dimer interface were determined via SiteMap. These sites were used in a virtual screening campaign that includes an integrated workflow of structure-based pharmacophore modeling, virtual screening, molecular docking, re-screening of common scaffolds to propose a series of compounds with different scaffolds as potential allosteric SK1 inhibitors. Finally, the stability of the SK1-ligand complexes was analyzed by molecular dynamics simulations. As a final outcome, ligand7 having a 4, 9-dihydro-1H-purine scaffold and ligand12 having a 2, 3, 4, 9-tetrahydro-1H-β-carboline scaffold were found to be potential selective inhibitors for SK1.