title: Activity-limiting role of molecular size: size-dependency of maximum activity for P450 inhibition as revealed by qHTS data.
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.
authors.affiliation: Diabetes Research Institute and Molecular and Cellular Pharmacology, Miller School of Medicine, University of Miami, Miami, Florida pbuchwald@med.miami.edu.
authors.forename: Peter
authors.initials: P
authors.lastname: Buchwald
mesh_terms: D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology*; D057166:High-Throughput Screening Assays
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors