Computation of brain-blood partitioning of organic solutes via free energy calculations

J Med Chem. 1996 Nov 22;39(24):4750-5. doi: 10.1021/jm960163r.


The ratio of brain-blood partitioning, log(Cbrain/Cblood) (log BB), of a series of compounds that range from simple solutes to histamine H2 antagonists was correlated with computed solvation free energy in water (delta G degree W). The free energies were computed with the AMSOL 5.0 program using the AM1-SM2.1 solvation model. From a set of 55 compounds, a function was developed in which log BB was related to the free energy of solvation as follows: log BB = 0.054 delta G degree W + 0.43 (r = 0.82 and standard error = 0.41). This correlation provided successful prediction of brain-blood partitioning for compounds outside the training dataset. Furthermore, for a set of 10 drugs, delta G degree W correlated well with literature data for the permeability of endothelial cell monolayers from bovine brain microvessels. In neuroscience drug discovery, the use of computed solvation free energies to predict brain penetration provides a facile method for prioritizing synthetic targets.

MeSH terms

  • Animals
  • Blood-Brain Barrier / physiology*
  • Brain / metabolism
  • Cattle
  • Cells, Cultured
  • Endothelium, Vascular / metabolism
  • Membrane Lipids / metabolism
  • Microcirculation / physiology
  • Molecular Conformation
  • Molecular Structure
  • Monte Carlo Method
  • Permeability
  • Pharmaceutical Preparations / chemistry
  • Pharmaceutical Preparations / metabolism*
  • Software
  • Solubility
  • Thermodynamics


  • Membrane Lipids
  • Pharmaceutical Preparations