Rules for Identifying Potentially Reactive or Promiscuous Compounds

This article describes a set of 275 rules, developed
over an 18-year
period, used to identify compounds that may interfere with biological
assays, allowing their removal from screening sets. Reasons for rejection
include reactivity (e.g., acyl halides), interference with assay measurements
(fluorescence, absorbance, quenching), activities that damage proteins
(oxidizers, detergents), instability (e.g., latent aldehydes), and
lack of druggability (e.g., compounds lacking both oxygen and nitrogen).
The structural queries were profiled for frequency of occurrence in
druglike and nondruglike compound sets and were extensively reviewed
by a panel of experienced medicinal chemists. As a means of profiling
the rules and as a filter in its own right, an index of biological
promiscuity was developed. The 584 gene targets with screening data
at Lilly were assigned to 17 subfamilies, and the number of subfamilies
at which a compound was active was used as a promiscuity index. For
certain compounds, promiscuous activity disappeared after sample repurification,
indicating interference from occult contaminants. Because this type
of interference is not amenable to substructure search, a “nuisance
list” was developed to flag interfering compounds that passed
the substructure rules.