Thermodynamic properties of leukotriene A 4 hydrolase inhibitors

Bioorg Med Chem. 2016 Nov 1;24(21):5243-5248. doi: 10.1016/j.bmc.2016.08.047. Epub 2016 Aug 26.

Abstract

The leukotriene A4 hydrolase (LTA4H) is a bifunctional enzyme, containing a peptidase and a hydrolase activity both activities having opposing functions regulating inflammatory response. The hydrolase activity is responsible for the conversion of leukotriene A4 to pro-inflammatory leukotriene B4, and hence, selective inhibitors of the hydrolase activity are of high pharmacological interest. Here we present the thermodynamic characterization of structurally distinct inhibitors of the LTA4H that occupy different regions of the binding site using different biophysical methods. An in silico method for the determination of stabilized water molecules in the binding site of the apo structure of LTA4H is used to interpret the measured thermodynamic data and provided insights for design of novel LTA4H inhibitors.

Keywords: Apo structure; LTA(4)H; Ligand binding; Water mapping.

MeSH terms

  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Epoxide Hydrolases / antagonists & inhibitors*
  • Epoxide Hydrolases / metabolism
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Structure-Activity Relationship
  • Thermodynamics*

Substances

  • Enzyme Inhibitors
  • Epoxide Hydrolases
  • leukotriene A4 hydrolase