Tautomer Standardization in Chemical Databases: Deriving Business Rules from Quantum Chemistry

Databases of small, potentially bioactive
molecules are ubiquitous
across the industry and academia. Designed such that each unique compound
should appear only once, the multiplicity of ways in which many compounds
can be represented means that these databases require methods for
standardizing the representation of chemistry. This is commonly achieved
through the use of “Chemistry Business Rules”, sets
of predefined rules that describe the “house style”
of the database in question. At Syngenta, the historical approach
to the design of chemistry business rules has been to focus on consistency
of representation, with chemical relevance given secondary consideration.
In this work, we overturn that convention. Through the use of quantum
chemistry calculations, we define a set of chemistry business rules
for tautomer standardization that reproduces gas-phase energetic preferences.
We go on to show that, compared to our historic approach, this method
yields tautomers that are in better agreement with those observed
experimentally in condensed phases and that are better suited for
use in predictive models.