The Valence State Combination Model: A Generic Framework for Handling Tautomers and Protonation States

The consistent handling of molecules
is probably the most basic
and important requirement in the field of cheminformatics. Reliable
results can only be obtained if the underlying calculations are independent
of the specific way molecules are represented in the input data. However,
ensuring consistency is a complex task with many pitfalls, an important
one being the fact that the same molecule can be represented by different
valence bond structures. In order to achieve reliability, a cheminformatics
system needs to solve two fundamental problems. First, different choices
of valence bond structures must be identified as the same molecule.
Second, for each molecule all valence bond structures relevant to
the context must be taken into consideration. The latter is especially
important with regard to tautomers and protonation states, as these
have considerable influence on physicochemical properties of molecules.
We present a comprehensive method for the rapid and consistent generation
of reasonable tautomers and protonation states for molecules relevant
in the context of drug design. This method is based on a generic scheme,
the Valence State Combination Model, which has been designed for the
enumeration and scoring of valence bond structures in large data sets.
In order to ensure our method’s consistency, we have developed
procedures which can serve as a general validation scheme for similar
approaches. The analysis of both the average number of generated structures
and the associated runtimes shows that our method is perfectly suited
for typical cheminformatics applications. By comparison with frequently
used and curated public data sets, we can demonstrate that the tautomers
and protonation state produced by our method are chemically reasonable.