In silico determination of orthosteric and allosteric inhibitors of sphingosine kinase 1 (SK1)

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. Even though the discovery of SK1 inhibitors has been considered as effective chemotherapeutic agents, early SK1 inhibitors that target the ATP or lipid-binding sites have suffered from poor potency, selectivity and pharmacokinetic properties. Thus, there is an urgent need for the discovery of in vivo stable orthosteric SK1 inhibitors with improved potency and selectivity. Also, the selectivity issue of the kinases, which share 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. Both the predicted putative allosteric site(s) and the lipid-binding site were used in an integrated workflow of ligand-based and structure-based pharmacophore modeling, virtual screening, molecular docking, re-screening of common scaffolds to propose a series of compounds with different scaffolds as potential orthosteric and allosteric SK1 inhibitors. The stability of the SK1-ligand complexes was analyzed by molecular dynamics simulations. As a final outcome, ligand 5 having a 1H-benzimidazol-2-ol scaffold was found to be a potential selective orthosteric inhibitor as well as ligand 7 having a 4,9-dihydro-1H-purine scaffold and ligand 12 sharing a 2,3,4,9-tetrahydro-1H-β-carboline scaffold were found to be potential selective allosteric inhibitors for SK1.