title: A quantitative structure-activity relationship and molecular graphics analysis of hydrophobic effects in the interactions of inhibitors with alcohol dehydrogenase.
abstract: 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.
mesh_terms: D000081:Acetamides / Q000378:metabolism; D000426:Alcohol Dehydrogenase; D000429:Alcohol Oxidoreductases / Q000037:antagonists & inhibitors*; D000818:Animals; D001596:Benzylamines / Q000378:metabolism; D003461:Crystallography; D004791:Enzyme Inhibitors / Q000378:metabolism*; D006736:Horses; D006801:Humans; D008099:Liver / Q000201:enzymology; D008433:Mathematics; D008958:Models, Molecular; D011720:Pyrazoles / Q000378:metabolism; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
chemical_list: D000081:Acetamides; D001596:Benzylamines; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D000429:Alcohol Oxidoreductases; D000426:Alcohol Dehydrogenase