Identification of Protein Fold Topology Shared between Different Folds Inhibited by Natural Products

Abstract

Natural products have withstood the test of time as therapeutics, but new lead-generation strategies have focussed away from natural products. A new approach that uses natural-product recognition to drive an understanding of biological space might provide an impetus for renewed focus on natural-product starting points. Protein fold topology (PFT) has been shown to be an underlying factor for natural-product recognition. An investigation of natural product inhibitors of the Zincin-like fold has demonstrated their capacity also to inhibit targets of different fold types. Analysis of crystal structure complexes for natural products cocrystallised within different fold types has shown similarity at the PFT level. Two new PFTT (where subscript T denotes PFT shared between therapeutic targets) relationships have been established: the Zincin-like- metallohydrolase/oxidoreductase PFTT and the Zincin-like-phosphorylase/hydrolase PFTT. The PFT relationship between a natural product's biosynthetic enzyme and therapeutic target, and now between different fold targets of the same natural product, suggests that PFT is the simplest descriptor of biological space. This fundamental factor for recognition could facilitate a rational approach to drug development guided by natural products.