RT Journal Article
SR Electronic
T1 Activity-Limiting Role of Molecular Size: Size-Dependency of Maximum Activity for P450 Inhibition as Revealed by qHTS Data
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1785
OP 1790
DO 10.1124/dmd.114.059717
VO 42
IS 11
A1 Peter Buchwald
YR 2014
UL http://dmd.aspetjournals.org/content/42/11/1785.abstract
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.