We built a metabolite structure predictor that rapidly enumerates trees of metabolic pathways. This algorithm–codenamed the metabolic forest—was built in python using the 2017.09.01 release of RDKIT, an open-source cheminformatics package.87 The metabolic forest included 24 reaction rules (Table 1 ). Each rule belonged to a ruleset, including (1) each of the five broad classes of phase I metabolism labeled in our simultaneous study,64 (link) (2) conjugation, (3) quinone formation, and (4) tautomerization. The conjugation and tautomerization rulesets encompass transformations that were sometimes implicitly included in our phase I and quinone formation datasets, perhaps due to experimental limitations.
For phase I metabolism, the stable oxygenation ruleset included the epoxidation, hydroxylation, nitrogen oxidation, and sulfur oxidation rules, the unstable oxygenation ruleset included the dealkylation and oxidation dehalogenation rules, the dehydrogenation ruleset included a lone dehydrogenation rule, the hydrolysis ruleset included the dephosphorylation, epoxide opening, carbonyl cleavage, and azo splitting rules, and the reduction ruleset included the benzodioxole reduction, dehydration, hydrogenation, nitrogen reduction, sulfur reduction, oxygen reduction, and reductive dehalogenation rules.
The conjugation ruleset included four rules specifying the reactions acetylation, glucuronidation, glutathionation, and sulfation.
The quinone formation ruleset included a single quinone formation rule that both modeled the two-electron oxidation that directly forms quinones and several types of reactions that often set the stage for that oxidation, such as aromatic hydroxylation.
Similarly, the tautomerization ruleset had a single eponymous rule. Tautomerization, although not generally regarded as a type of metabolism, nevertheless plays a role in known metabolic pathways of drugs like clopidogrel88 (link) and ranitidine.89 (link)Programmatically, these rules fell into three archetypes: SMARTS rules, resonance pair rules, and resonance structure rules, detailed in the following sections.
For phase I metabolism, the stable oxygenation ruleset included the epoxidation, hydroxylation, nitrogen oxidation, and sulfur oxidation rules, the unstable oxygenation ruleset included the dealkylation and oxidation dehalogenation rules, the dehydrogenation ruleset included a lone dehydrogenation rule, the hydrolysis ruleset included the dephosphorylation, epoxide opening, carbonyl cleavage, and azo splitting rules, and the reduction ruleset included the benzodioxole reduction, dehydration, hydrogenation, nitrogen reduction, sulfur reduction, oxygen reduction, and reductive dehalogenation rules.
The conjugation ruleset included four rules specifying the reactions acetylation, glucuronidation, glutathionation, and sulfation.
The quinone formation ruleset included a single quinone formation rule that both modeled the two-electron oxidation that directly forms quinones and several types of reactions that often set the stage for that oxidation, such as aromatic hydroxylation.
Similarly, the tautomerization ruleset had a single eponymous rule. Tautomerization, although not generally regarded as a type of metabolism, nevertheless plays a role in known metabolic pathways of drugs like clopidogrel88 (link) and ranitidine.89 (link)Programmatically, these rules fell into three archetypes: SMARTS rules, resonance pair rules, and resonance structure rules, detailed in the following sections.
