Structural Searching of Biosynthetic Enzymes to Predict Protein Targets of Natural Products

Recently, we have demonstrated that site comparison methodology using flavonoid biosynthetic enzymes as the query could automatically identify structural features common to different flavonoid-binding proteins, allowing for the identification of flavonoid targets such as protein kinases. With the aim of further validating the hypothesis that biosynthetic enzymes and therapeutic targets can contain a similar natural product imprint, we collected a set of 159 crystallographic structures representing 38 natural product biosynthetic enzymes by searching the Protein Databank. Each enzyme structure was used as a query to screen a repository of approximately 10 000 ligandable sites by active site similarity. We report a full analysis of the screening results and highlight three retrospective examples where the natural product validates the method, thereby revealing novel structural relationships between natural product biosynthetic enzymes and putative protein targets of the natural product. From a prospective perspective, our work provides a list of up to 64 potential novel targets for 25 well-characterized natural products.