tautomers - Enumeration

Canonicalization

The OEEnumerateTautomers function is used for canonicalizing and/or enumerating the tautomeric forms of a small molecule. Canonicalization converts any of the tautomeric forms of a given molecule into a single unique representation. This is useful for database registration where alternate representations of tautomeric compounds often leads to duplicate entries in a database.

Some effort is made by the OEEnumerateTautomers function to direct the “canonical” representation to be a physiologically preferred form. However, there are no guarantees the tautomer selected is indeed the lowest energy and, indeed, solvent effects, etc., preclude there being a single “best” form of a tautomer. Fortunately, this is not necessary for database work.

OEEnumerateTautomers is not a conformer generation function and will not create coordinates for molecules that are read in with no coordinates. When used on molecules with three-dimensional coordinates, OEEnumerateTautomers attempts to place hydrogens in a reasonable manner. However, OEEnumerateTautomers does not modify the heavy-atom coordinates of the molecule. In cases where the change in tautomer-state dictates a change in conformation, one will need to use a conformer-generation tool (such as OMEGA) to generate reasonable conformations for the output from tautomers. We recommend that in the preparation of small-molecules for study, charge-state and tautomer enumeration be performed before conformer generation.

Reasonable Ranking

By default, OEEnumerateTautomers will return the canonical tautomer as the first molecule in the iterator. However, if OETautomerOptions::SetRankTautomers is set to true, OEEnumerateTautomers will attempt to provide a low-energy, medicinally-relevant “reasonable” tautomer. Since it is not feasible on an informatics time-scale to correctly predict tautomer ratios, the “reasonable” tautomer is a good trade-off for generating a tautomeric form that is suitable for depiction for chemists.

The following depictions are a useful guide to knowing what tautomers are favored as “reasonable”:

  • Conversion of carboxylates to diols and nitros to di-hydroxy amines is very unfavorable.

  • Generation of unnecessary, non-dative, formal charges is unfavorable.

  • Exocyclic bonds adjacent to aromatic rings are accounted for.

  • Priority is given to aliphatic double bond positions.