PT - JOURNAL ARTICLE AU - Peter Buchwald TI - Activity-Limiting Role of Molecular Size: Size-Dependency of Maximum Activity for P450 Inhibition as Revealed by qHTS Data AID - 10.1124/dmd.114.059717 DP - 2014 Nov 01 TA - Drug Metabolism and Disposition PG - 1785--1790 VI - 42 IP - 11 4099 - http://dmd.aspetjournals.org/content/42/11/1785.short 4100 - http://dmd.aspetjournals.org/content/42/11/1785.full SO - Drug Metab Dispos2014 Nov 01; 42 AB - 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.