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 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 nuiance list was developed to flag interfering compounds that passed the substructure rules.