Searching for bioisosteric replacements is a valuable part of a medicinal chemist's toolbox. A bioisosteric core replacement can solve an ADMET or IP issue and move development into a new lead series, while bioisosteric replacements for leaf groups enable fine tuning of molecular properties without affecting the fundamental activity.A fundamental limitation of most current bioisosteric replacement search tools is the synthesisability of their suggestions. Existing computational synthesizability assessments tend to perform poorly in this context. We present an alternative approach in which the chemist is able to define the accessible synthetic space around the core of their lead molecule. The search for bioisosteres is confined to this space, so that the results are all known to be synthesisable using accessible reagents. In order to do this, multiple databases of fragments are created from the reagent sets and classified according to the synthons present and the desired chemistries.Despite the very large number of chemical reactions in the modern medicinal chemistry tool set, we have found that a very limited number of synthetic transforms are needed to fully represent this space. By focusing on the structural transformation rather than the chemical reaction, many different chemistries can be summarized into a small set of rules.We implement these rules in a special-purpose chemical transformation language, ATPAT. The ATPAT language combines a molecular regular expression syntax that is simpler, more extensible and more powerful than SMARTS with a set of simple transformation procedures that can be automatically applied on a successful match. The ATPAT engine allows new chemical transformation rules to be generated effortlessly.The result is an integrated system that allows the chemist to easily process his or her available reagents into a list of potential molecules to make. Wrapping this system in a KNIME or Pipeline Pilot wrapper allows automation and simple integration into existing cheminformatics systems.

Bioisosteres in accessible chemistry space

248th National Meeting (2014)

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