Structure-based design of biocatalytic panels for pharmaceuticals synthesis

Biocatalysis is emerging as an attractive option for manufacturing pharmaceuticals. However, the identification of enzymes for target transformations of interest requires major screening efforts. Here we report a structure-based computational workflow to prioritize protein sequences by a score based on predicted activities on substrates, thereby reducing resource intensive laboratory-based biocatalyst screening. We selected imine reductases (IREDs) as a class of biocatalysts to illustrate the application of the computational workflow termed IREDFisher. Validation by using published data showed that IREDFisher can retrieve the best enzymes and increase the hit rate by identifying the top 20 ranked sequences. The power of IREDFisher is confirmed by computationally screening 1,400 sequences to identify suitable biocatalysts for five selected reductive amination reactions. IREDFisher is available as a user-friendly web interface that will enable rapid identification of biocatalysts for applications in synthesis and directed evolution studies with minimal time and resource expenditure.