Get Your Atoms in OrderAn Open-Source Implementation of a Novel and Robust Molecular Canonicalization Algorithm

Finding a canonical
ordering of the atoms in a molecule is a prerequisite
for generating a unique representation of the molecule. The canonicalization
of a molecule is usually accomplished by applying some sort of graph
relaxation algorithm, the most common of which is the Morgan algorithm.
There are known issues with that algorithm that lead to noncanonical
atom orderings as well as problems when it is applied to large molecules
like proteins. Furthermore, each cheminformatics toolkit or software
provides its own version of a canonical ordering, most based on unpublished
algorithms, which also complicates the generation of a universal unique
identifier for molecules. We present an alternative canonicalization
approach that uses a standard stable-sorting algorithm instead of
a Morgan-like index. Two new invariants that allow canonical ordering
of molecules with dependent chirality as well as those with highly
symmetrical cyclic graphs have been developed. The new approach proved
to be robust and fast when tested on the 1.45 million compounds of
the ChEMBL 20 data set in different scenarios like random renumbering
of input atoms or SMILES round tripping. Our new algorithm is able
to generate a canonical order of the atoms of protein molecules within
a few milliseconds. The novel algorithm is implemented in the open-source
cheminformatics toolkit RDKit. With this paper, we provide a reference
Python implementation of the algorithm that could easily be integrated
in any cheminformatics toolkit. This provides a first step toward
a common standard for canonical atom ordering to generate a universal
unique identifier for molecules other than InChI.