Figure 10.

Reactivity scores identify non-obvious, reactive motifs not captured by PAINS filters. (A) The het_thio_666 PAINS filter group consists of tricyclic, heteroaromatic, sulfur-containing compounds. Twenty-four of 44 bioassay promiscuous compounds matching this filter group in PubChem also contain tertiary amine rings such as piperidines, piperazines, or pyrrolidines. (B) Among compounds matching this PAINS filter group, site-level cyanide reactivity scores are nonzero only on the atoms not matched by the filter group, suggesting a reactive mechanism unrelated to the motifs in this filter group. (C) Cyclic tertiary amines are known to be oxidized in vivo by Cytochrome P450 enzymes.^66,67 This oxidation leads to the formation of an iminium ion intermediate that can react with cyanide or biological substrates. ***: p < 0.0001.