Similarity between Flavonoid Biosynthetic Enzymes and Flavonoid Protein Targets Captured by Three-Dimensional Computing Approach

Natural products are made by nature through interaction with biosynthetic enzymes. They also exert their effect as drugs by interaction with proteins. To address the question Do biosynthetic enzymes and therapeutic targets share common mechanisms for the molecular recognition of natural products?, we compared the active site of five flavonoid biosynthetic enzymes to 8077 ligandable binding sites in the Protein Data Bank using two three-dimensional-based methods (SiteAlign and Shaper). Virtual screenings efficiently retrieved known flavonoid targets, in particular protein kinases. A consistent performance obtained for variable site descriptions (presence/absence of water, variable boundaries, or small structural changes) indicated that the methods are robust and thus well suited for the identification of potential target proteins of natural products. Finally, our results suggested that flavonoid binding is not primarily driven by shape, but rather by the recognition of common anchoring points.