Health & Environmental Research Online (HERO)


Print Feedback Export to File
3841193 
Journal Article 
Rules for identifying potentially reactive or promiscuous compounds 
Bruns, RF; Watson, IA 
2012 
Yes 
Journal of Medicinal Chemistry
ISSN: 0022-2623
EISSN: 1520-4804 
55 
22 
9763-9772 
English 
23061697 
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. 
Animals; Biological Assay/standards; Drug Discovery/standards; High-Throughput Screening Assays/standards; Molecular Structure; Pharmaceutical Preparations/chemistry/metabolism; Structure-Activity Relationship; Toxicity Tests/standards