Bacterial versus human sphingosine-1-phosphate lyase (S1PL) in the design of potential S1PL inhibitors

Bioorg Med Chem. 2016 Sep 15;24(18):4381-4389. doi: 10.1016/j.bmc.2016.07.033. Epub 2016 Jul 18.


A series of potential active-site sphingosine-1-phosphate lyase (S1PL) inhibitors have been designed from scaffolds 1 and 2, arising from virtual screening using the X-ray structures of the bacterial (StS1PL) and the human (hS1PL) enzymes. Both enzymes are very similar at the active site, as confirmed by the similar experimental kinetic constants shown by the fluorogenic substrate RBM13 in both cases. However, the docking scoring functions used probably overestimated the weight of electrostatic interactions between the ligands and key active-site residues in the protein environment, which may account for the modest activity found for the designed inhibitors. In addition, the possibility that the inhibitors do not reach the enzyme active site should not be overlooked. Finally, since both enzymes show remarkable structural differences at the access channel and in the proximity to the active site cavity, caution should be taken when designing inhibitors acting around that area, as evidenced by the much lower activity found in StS1PL for the potent hS1PL inhibitor D.

Keywords: Design; Docking; Inhibitors; Lyase; Sphingolipids.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehyde-Lyases / antagonists & inhibitors*
  • Bacteria / enzymology
  • Carbon-13 Magnetic Resonance Spectroscopy
  • Crystallography, X-Ray
  • Drug Design
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Mass Spectrometry
  • Molecular Structure
  • Proton Magnetic Resonance Spectroscopy


  • Enzyme Inhibitors
  • Aldehyde-Lyases
  • sphingosine 1-phosphate lyase (aldolase)