A practical use of ligand efficiency indices out of the fragment-based approach: ligand efficiency-guided lead identification of soluble epoxide hydrolase inhibitors

J Med Chem. 2011 Feb 10;54(3):851-7. doi: 10.1021/jm101273e. Epub 2010 Dec 30.


Ligand efficiency is frequently used to evaluate fragment compounds in fragment-based drug discovery. We applied ligand efficiency indices in a conventional virtual screening-initiated lead generation study of soluble epoxide hydrolase inhibitors. From a considerable number of screening hits, we carefully selected a compound exhibiting relatively weak inhibitory activity but high ligand efficiency. This ligand efficiency-guided selection could reveal compounds possessing preferable lead-like characteristics in terms of molecular size and lipophilicity. The following hit-to-lead medicinal chemistry campaign successfully led to a more potent, ADMET-clean, lead-like compound preserving high ligand efficiency. Retrospective analyses, including consideration of the more recently proposed indices of ligand efficiency, shed light on the validity of our hit triage and hit-to-lead studies. The present work proposes a practical methodology for lead generation using the concept of ligand efficiency.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Databases, Factual
  • Epoxide Hydrolases / antagonists & inhibitors*
  • Epoxide Hydrolases / chemistry
  • Hep G2 Cells
  • Humans
  • Ligands
  • Molecular Conformation
  • Oxadiazoles / chemical synthesis
  • Oxadiazoles / chemistry*
  • Oxadiazoles / pharmacology
  • Protein Binding
  • Quantitative Structure-Activity Relationship*
  • Solubility
  • Stereoisomerism
  • Urea / analogs & derivatives*
  • Urea / chemical synthesis
  • Urea / chemistry
  • Urea / pharmacology
  • Young Adult


  • 4-(3-isopropyl-1,2,4-oxadiazol-5-yl)-N-(trans-2-phenylcyclopropyl)piperidine-1-carboxamide
  • Ligands
  • Oxadiazoles
  • Urea
  • Epoxide Hydrolases