Rules for Identifying Potentially Reactive or Promiscuous Compounds

Abstract

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.

ADME-Tox profiles of some food additives and pesticides

“…However, we note that some additives show adverse effects [22]. For example, guanylic acid (as it is metabolized in purines) should be avoided by asthmatic people and by people suffering from gout.…”

“…This table contains the European number (E-number), the descriptors extracted from FAFDrugs2 server, their functions and known side effects [22]. The pesticides considered in this study are presented in the table 2.…”

Two new sacrolide-class oxylipins from the edible cyanobacterium Aphanothece sacrum

“…8,9 Sacrolide A belongs to the same oxylipin class, but loss of the activity upon epimerization of C9 suggests that it is more of a target-specific inhibitor than promiscuous Michael acceptor. 10 Conservation of an S-configuration at C13 among sacrolide A, 1 and 2 implies that hydroxylation of this carbon is an enzymatic process. In contrast, variation in the chirality of C9 carbinol and the degree of unsaturation at C15 is allowed, underpinning a non-enzymatic formation of α,β-unsaturated-γ-ketol from 12,13-allene oxide precursors (Supplementary Scheme S7).…”

Beyond PAINs: Chemotype Sensitivity of Protein Methyltransferases in Screens

“…Of these, 193 (68%) compounds displayed promiscuous behavior by hitting proteins within four or more gene families or by being active in more than 60 individual assays. 17 Compounds displaying general promiscuity can be reactive compounds, aggregators, or contain impurities. 10,17 Table 2 lists three examples.…”

“…17 Compounds displaying general promiscuity can be reactive compounds, aggregators, or contain impurities. 10,17 Table 2 lists three examples. Some general promiscuous compounds could be identified using rules such as PAINS.…”