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.