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In Silico Characterization of Structural Distinctions between Isoforms of Human and Mouse Sphingosine Kinases for Accelerating Drug Discovery

“…Additionally, the difference in results between in vitro and in vivo assays for orthologues of each SphK isoform 14 is unexpected but provides a pathway to rationalize current experimental results on inhibitor efficacy. 39 Specifically, our investigation aimed to (1) interrogate how variation in key residues in the Sph binding cavities among isoforms and across orthologues affects the binding site shape, volume, and lipophilicity and ( 2) identify intermolecular interactions that can be exploited to improve inhibitors as based on known experimental inhibitor selectivity and molecular docking results.…”

“…PF-543 is hSphK1 selective (100-fold) with a K i of 4.3 nM in hSphK1, 19 and SLP7111228 is hSphK1 selective inhibitor with a K i of 48 nM. 39 Docking results of PF-543 showed selectivity for hSphK1 when compared to mSphK1 based on our ranking of important interactions and distance measurements (Figure 6). The poses of PF-543 in hSphK2 and mSphK2 do not support selectivity for SphK 2s.…”

“…Typically, inhibitors that have been studied have a large aromatic substituent (phenyl or naphthyl ring) in this portion of the ligand, with an additional methylene moiety between polar and hydrophobic regions of the inhibitor that can "switch" selectivity (e.g., compound SLP7111228) to be more hSphK1 selective relative to hSphK2. 39 Further adding to the role of residue 174 in selectivity, an internal phenyl ring with no additional methylene moiety was found to be essential in hSphK2 selectivity. 17 Given the lack of a hydrophobic characteristic in mSphK2 in the core of the sphingosine binding cavity, it is unsurprising that no inhibitors have currently been generated that selectively target this orthologue based on our receptor-based pharmacophore model for mSphK2.…”