Evaluation of dynamic polar molecular surface area as predictor of drug absorption: comparison with other computational and experimental predictors

J Med Chem. 1998 Dec 31;41(27):5382-92. doi: 10.1021/jm980313t.


The relationship between various molecular descriptors and transport of drugs across the intestinal epithelium was evaluated. The monolayer permeability (Pc) of human intestinal Caco-2 cells to a series of nine beta-receptor-blocking agents was investigated in vitro. The dynamic polar molecular surface area (PSAd) of the compounds was calculated from all low-energy conformations identified in molecular mechanics calculations in vacuum and in simulated chloroform and water environments. For most of the investigated drugs, the effects of the different environments on PSAd were small. The exception was H 216/44, which is a large flexible compound containing several functional groups capable of hydrogen bonding (PSAd,chloroform = 70.8 A2 and PSAd,water = 116.6 A2). The relationship between Pc and PSAd was stronger than those between Pc and the calculated octanol/water distribution coefficients (log Dcalc) or the experimentally determined immobilized liposome chromatography (ILC) retention. Pc values for two new practolol analogues and H 216/44 were predicted from the structure-permeability relationships of a subset of the nine compounds and compared with experimental values. The Pc values of the two practolol analogues were predicted well from both PSAd calculations and ILC retention studies. The Pc value of H 216/44 was reasonably well-predicted only from the PSAd of conformations preferred in vacuum and in water. The other descriptors overestimated the Pc of H 216/44 100-500-fold.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-Antagonists / chemical synthesis
  • Adrenergic beta-Antagonists / chemistry
  • Adrenergic beta-Antagonists / metabolism*
  • Amides / chemical synthesis
  • Amides / chemistry
  • Amides / metabolism*
  • Biological Transport
  • Caco-2 Cells
  • Chromatography, Liquid / methods
  • Drug Design*
  • Epithelial Cells / metabolism
  • Formamides / chemical synthesis
  • Formamides / chemistry
  • Formamides / metabolism*
  • Humans
  • Intestinal Absorption*
  • Liposomes
  • Models, Molecular*
  • Molecular Conformation
  • Monte Carlo Method
  • Permeability
  • Propanolamines / chemical synthesis
  • Propanolamines / chemistry
  • Propanolamines / metabolism*
  • Structure-Activity Relationship


  • Adrenergic beta-Antagonists
  • Amides
  • Formamides
  • H 224-45
  • H 95-71
  • Liposomes
  • Propanolamines