Computer-aided synthesis planning (CASP) tools have revolutionized the way chemists approach the design of synthesis routes. However, these tools often overlook biocatalytic reactions, which offer significant selectivity and sustainability benefits over traditional chemical methods. Previously we reported a CASP tool specifically for biocatalysis, named RetroBioCat, showing it could design enzyme cascades as reported in the biocatalysis literature. Here we expand RetroBioCat, combining our tool with other approaches across chemistry and biosynthesis, enabling route design utilising reactions from all domains (Figure 1).

We present a highly parametrizable route searching algorithm, built upon the Monto Carlo tree search with various methods to combine and rank reactions from different domains. To evaluate this approach, we discuss benchmarking results against a range of target molecules, utilising different retrosynthetic expansion approaches from across biocatalysis, biosynthesis, and chemistry, under various parameter settings. Finally, we discuss the user experience of scientists utilising this tool for the design of synthesis routes to pharmaceutical molecules, with selected examples carried out in the lab. Enzyme selection and reaction feasibility prediction are shown to be critical, with methods to augment human decision making in this area explored.

In summary, we present the next generation of tools on the RetroBioCat platform, allowing scientists to design routes which make intelligent use of enzymes alongside organic chemistry, putting biocatalysis knowledge at the fingertips of scientists, and promoting the use of enzymes for more sustainable and economic synthesis routes.

Figure 1 – A CASP tool combining chemical and biological steps

Sabine Flitsch

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