Electron density guided fragment-based lead discovery of ketohexokinase inhibitors

J Med Chem. 2010 Nov 25;53(22):7979-91. doi: 10.1021/jm100677s. Epub 2010 Oct 29.


A fragment-based drug design paradigm has been successfully applied in the discovery of lead series of ketohexokinase inhibitors. The paradigm consists of three iterations of design, synthesis, and X-ray crystallographic screening to progress low molecular weight fragments to leadlike compounds. Applying electron density of fragments within the protein binding site as defined by X-ray crystallography, one can generate target specific leads without the use of affinity data. Our approach contrasts with most fragment-based drug design methodology where solution activity is a main design guide. Herein we describe the discovery of submicromolar ketohexokinase inhibitors with promising druglike properties.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Caco-2 Cells
  • Cell Membrane Permeability
  • Crystallography, X-Ray
  • Electrons
  • Fructokinases / antagonists & inhibitors*
  • Humans
  • In Vitro Techniques
  • Indazoles / chemical synthesis*
  • Indazoles / chemistry
  • Indazoles / pharmacokinetics
  • Male
  • Microsomes, Liver / metabolism
  • Models, Molecular*
  • Molecular Structure
  • Piperidines / chemical synthesis*
  • Piperidines / chemistry
  • Piperidines / pharmacokinetics
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship


  • Indazoles
  • N-(3-(methylthio)-1-phenyl-1H-indazol-6-yl)piperidine-4-carboxamide
  • Piperidines
  • Fructokinases
  • ketohexokinase

Associated data

  • PDB/3NBV
  • PDB/3NBW
  • PDB/3NC2
  • PDB/3NC9
  • PDB/3NCA