Rationalizing the activities of diverse cholecystokinin 2 receptor antagonists using molecular field points

J Med Chem. 2008 Feb 14;51(3):565-73. doi: 10.1021/jm070880t. Epub 2008 Jan 18.


Cholecystokinin 2 receptor antagonists encompass a wide range of structures. This makes them unsuitable candidates for existing 3D-QSAR methods and has led us to develop an alternative approach to account for their observed biological activities. A diverse set of 21 antagonists was subjected to a novel molecular field-based similarity analysis. The hypothesis is that compounds with similar field patterns will bind at the same target site regardless of their underlying structure. This initial report demonstrates a linear correlation between ligand similarity and biological activity for this challenging data set. A model generated with three molecules was used to predict the activity of 18 test compounds, with different chemotypes, with a root-mean-square error of 0.68 pKB units. The ability to automatically derive a molecular alignment without knowledge of the protein structure represents an improvement over existing pharmacophore methods and makes the method particularly suitable for scaffold-hopping.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzoates / chemistry
  • Benzoates / pharmacology
  • Binding Sites
  • Binding, Competitive
  • Bridged-Ring Compounds / chemistry
  • Bridged-Ring Compounds / pharmacology
  • Cyclohexanes / chemistry
  • Cyclohexanes / pharmacology
  • Gastric Mucosa / metabolism
  • Guinea Pigs
  • Heterocyclic Compounds, 2-Ring / chemistry
  • Heterocyclic Compounds, 2-Ring / pharmacology
  • Hydrophobic and Hydrophilic Interactions
  • In Vitro Techniques
  • Least-Squares Analysis
  • Ligands
  • Linear Models
  • Models, Molecular
  • Pancreas / cytology
  • Phthalic Acids / chemistry
  • Phthalic Acids / pharmacology
  • Quantitative Structure-Activity Relationship*
  • Radioligand Assay
  • Rats
  • Receptor, Cholecystokinin A / antagonists & inhibitors
  • Receptor, Cholecystokinin B / antagonists & inhibitors*
  • Receptor, Cholecystokinin B / chemistry*


  • Benzoates
  • Bridged-Ring Compounds
  • Cyclohexanes
  • Heterocyclic Compounds, 2-Ring
  • Ligands
  • Phthalic Acids
  • Receptor, Cholecystokinin A
  • Receptor, Cholecystokinin B