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

Authors:
  • CHCorwin Hansch
    Corwin Hansch
  • TKTeri Klein
    Teri Klein
  • JMJudith McClarin
    Judith McClarin
  • RLRobert Langridge
    Robert Langridge
  • NCNeal W. Cornell
    Neal W. Cornell
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Abstract
An analysis of the inhibition constants of pyrazoles, phenylacetamides, formylbenzylamines, and acetamides acting on liver alcohol dehydrogenase (ADH) yields quantitative structure-activity relationship (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 cystallographic 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.