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Rapid CommunicationShort Communication

Activity-Limiting Role of Molecular Size: Size-Dependency of Maximum Activity for P450 Inhibition as Revealed by qHTS Data

Peter Buchwald
Drug Metabolism and Disposition November 2014, 42 (11) 1785-1790; DOI: https://doi.org/10.1124/dmd.114.059717
Peter Buchwald
Diabetes Research Institute and Molecular and Cellular Pharmacology, Miller School of Medicine, University of Miami, Miami, Florida
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Abstract

Analysis of a large number of data on cytochrome P450 (P450) inhibition obtained from quantitative high-throughput screening assays from the PubChem BioAssay Database clearly indicates that molecular size has an important activity-limiting role for datasets focused on drug-like compounds (PubChem BioAssay Identifier [AID] 1851) as well as for datasets also incorporating a wider range of environmental chemicals (AIDs 410, 899, 883, 891, and 884). Maximum inhibitory activity increases with size for small enough structures then plateaus and begins to show a decreasing trend for larger structures. Log-scaled maximum median inhibitory concentration (pIC50) as a function of molecular size could be fitted well with a bilinear model (LinBiExp), and the shape of the curve is quite similar across five P450 isozymes (CYP1A2, 2C9, 2C19, 2D6, and 3A4) with a turning-point of maximum inhibition around 300–500 Da. While the present size-based approach cannot account for the variability of activity in general, using data for a very large number of compounds, it still provides an intuitive interpretation of the maximum P450-inhibitory activity obtainable for a given molecular size and highlights the presence of an “optimum” size range.

Footnotes

    • Received June 25, 2014.
    • Accepted August 20, 2014.
  • dx.doi.org/10.1124/dmd.114.059717.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 42 (11)
Drug Metabolism and Disposition
Vol. 42, Issue 11
1 Nov 2014
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Rapid CommunicationShort Communication

Size-Dependency of Maximum Activity for P450 Inhibition

Peter Buchwald
Drug Metabolism and Disposition November 1, 2014, 42 (11) 1785-1790; DOI: https://doi.org/10.1124/dmd.114.059717

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Rapid CommunicationShort Communication

Size-Dependency of Maximum Activity for P450 Inhibition

Peter Buchwald
Drug Metabolism and Disposition November 1, 2014, 42 (11) 1785-1790; DOI: https://doi.org/10.1124/dmd.114.059717
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