A quantitative structure-activity relationship and molecular graphics analysis of hydrophobic effects in the interactions of inhibitors with alcohol dehydrogenase

J Med Chem. 1986 May;29(5):615-20. doi: 10.1021/jm00155a005.


An analysis of the inhibition constants of pyrazoles, phenylacetamides, formylbenzylamines, and acetamides acting on liver alcohol dehydrogenase (ADH) yields quantitative structure-activity relationships (QSAR) having a linear dependency on octanol-water partition coefficients (log P). The average coefficient and standard deviation with the log P term for six different QSAR is 0.96 (+/- 0.14). This suggests complete desolvation of the substituents (directly comparable to partitioning into octanol) on binding to the enzyme. Study of a molecular graphics model of ADH constructed from the X-ray crystallographic coordinates shows that the substituents are engulfed in a long hydrophobic channel which is so narrow that water of solvation must be removed from them in the binding process.

Publication types

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

MeSH terms

  • Acetamides / metabolism
  • Alcohol Dehydrogenase
  • Alcohol Oxidoreductases / antagonists & inhibitors*
  • Animals
  • Benzylamines / metabolism
  • Crystallography
  • Enzyme Inhibitors / metabolism*
  • Horses
  • Humans
  • Liver / enzymology
  • Mathematics
  • Models, Molecular
  • Pyrazoles / metabolism
  • Structure-Activity Relationship
  • X-Ray Diffraction


  • Acetamides
  • Benzylamines
  • Enzyme Inhibitors
  • Pyrazoles
  • Alcohol Oxidoreductases
  • Alcohol Dehydrogenase