Evaluation of structure-derived pharmacophore of soluble epoxide hydrolase inhibitors by virtual screening

Bioorg Med Chem Lett. 2012 Nov 1;22(21):6762-5. doi: 10.1016/j.bmcl.2012.08.066. Epub 2012 Aug 23.

Abstract

The soluble epoxide hydrolase (sEH) is an enzyme located downstream of the CYP 450 branch of the arachidonic acid cascade and can be linked to a number of indications, including cardiovascular disorders, diabetes and inflammatory processes. Numerous inhibitors (sEHI) have been reported, mostly based on urea or amide scaffolds. The search for valid bioisosteric replacements is an ongoing challenge in the discovery of sEHI. We developed a receptor-based pharmacophore model on the basis of 13 crystal structures of the sEH and performed a virtual screening for novel compounds. The virtual screening hits were verified in vitro proving the basic applicability of the model and leading to novel non-urea sEHI.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminopyridines / chemical synthesis
  • Aminopyridines / chemistry*
  • Computer Simulation*
  • Crystallography, X-Ray
  • Drug Design*
  • Enzyme Inhibitors / chemistry*
  • Epoxide Hydrolases / antagonists & inhibitors*
  • Models, Biological
  • Solubility
  • Structure-Activity Relationship

Substances

  • Aminopyridines
  • Enzyme Inhibitors
  • Epoxide Hydrolases