Format

Send to

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

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

Author information

1
Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Research Unit on Bioactive Molecules (RUBAM), Department of Biomedicinal Chemistry, Jordi Girona 18-26, E-08034 Barcelona, Spain; University of Barcelona (UB), Faculty of Pharmacy, Department of Pharmacology, Toxicology and Medicinal Chemistry, Unit of Pharmaceutical Chemistry (Associated Unit to CSIC), Avga. Joan XXIII s/n, E-08028 Barcelona, Spain.
2
Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Research Unit on Bioactive Molecules (RUBAM), Department of Biomedicinal Chemistry, Jordi Girona 18-26, E-08034 Barcelona, Spain.
3
Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Department of Biological Chemistry and Molecular Modeling, Jordi Girona 18-26, E-08034 Barcelona, Spain. Electronic address: jordi.bujons@iqac.csic.es.
4
Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Research Unit on Bioactive Molecules (RUBAM), Department of Biomedicinal Chemistry, Jordi Girona 18-26, E-08034 Barcelona, Spain; University of Barcelona (UB), Faculty of Pharmacy, Department of Pharmacology, Toxicology and Medicinal Chemistry, Unit of Pharmaceutical Chemistry (Associated Unit to CSIC), Avga. Joan XXIII s/n, E-08028 Barcelona, Spain. Electronic address: delgado@rubam.net.

Abstract

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

PMID:
27475537
DOI:
10.1016/j.bmc.2016.07.033
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center