Novel method for generating structure-based pharmacophores using energetic analysis

J Chem Inf Model. 2009 Oct;49(10):2356-68. doi: 10.1021/ci900212v.


We describe a novel method to develop energetically optimized, structure-based pharmacophores for use in rapid in silico screening. The method combines pharmacophore perception and database screening with protein-ligand energetic terms computed by the Glide XP scoring function to rank the importance of pharmacophore features. We derive energy-optimized pharmacophore hypotheses for 30 pharmaceutically relevant crystal structures and screen a database to assess the enrichment of active compounds. The method is compared to three other approaches: (1) pharmacophore hypotheses derived from a systematic assessment of receptor-ligand contacts, (2) Glide SP docking, and (3) 2D ligand fingerprint similarity. The method developed here shows better enrichments than the other three methods and yields a greater diversity of actives than the contact-based pharmacophores or the 2D ligand similarity. Docking produces the most cases (28/30) with enrichments greater than 10.0 in the top 1% of the database and on average produces the greatest diversity of active molecules. The combination of energy terms from a structure-based analysis with the speed of a ligand-based pharmacophore search results in a method that leverages the strengths of both approaches to produce high enrichments with a good diversity of active molecules.

MeSH terms

  • Computational Biology
  • Crystallography, X-Ray
  • Databases, Protein
  • Drug Evaluation, Preclinical / methods*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Hydrogen Bonding
  • Hydrophobic and Hydrophilic Interactions
  • Ligands
  • Models, Molecular
  • Molecular Conformation
  • Proteins / antagonists & inhibitors
  • Proteins / chemistry
  • Proteins / metabolism
  • Thermodynamics*


  • Enzyme Inhibitors
  • Ligands
  • Proteins