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Related Experiment Videos

Hydrogen-bonding parameter and its significance in quantitative structure--activity studies

T Fujita, T Nishioka, M Nakajima

    Journal of Medicinal Chemistry
    |August 1, 1977
    PubMed
    Summary

    Quantitative structure-activity relationship (QSAR) models require an extra parameter to account for differing drug hydrogen-bonding effects between biological sites and reference phases. This parameter helps refine predictions of biological activity by considering specific drug-target interactions.

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    Mutation research·1995

    Area of Science:

    • Medicinal Chemistry
    • Computational Chemistry
    • Pharmacology

    Background:

    • Hydrophobicity is crucial for drug partitioning, often estimated using 1-octanol-water systems.
    • Hydrogen-bonding interactions at the biological target site may differ significantly from those in reference partitioning phases.
    • This discrepancy necessitates adjustments in quantitative structure-activity relationship (QSAR) models, specifically Hansch-type correlations.

    Purpose of the Study:

    • To introduce and analyze a parameter accounting for the differential hydrogen-bonding effects in QSAR.
    • To refine Hansch-type correlations by incorporating an 'extra' hydrogen-bonding term.
    • To improve the prediction of biological activity for drug series with varying hydrogen-bonding capabilities.

    Main Methods:

    Related Experiment Videos

  • Analysis of the ratio of hydrogen-bonding association constants between biological and organic phases.
  • Evaluation of the ratio of molarities of hydrogen-bonding species in biological and organic phases.
  • Development of an indicator variable to represent the 'extra' hydrogen-bonding effect when association constants are similar.

    • Main Results:

    • The 'extra' hydrogen-bonding effect can be quantified by the ratio of association constants and molarities.
    • In cases where association constants are similar, an indicator variable effectively captures the effect.
    • The slope of the indicator variable correlates with the molarity ratio of hydrogen-bonding species.

    Conclusions:

    • A specific parameter is required in Hansch-type correlations when drug hydrogen-bonding differs between biological action sites and partitioning phases.
    • This parameter, often an indicator variable, improves the accuracy of QSAR models for drug activity prediction.
    • The approach is particularly relevant for substituents with significant hydrogen-bonding capabilities in congeneric series.