Natural product-like chemical space: search for chemical dissectors of macromolecular interactions

Abstract

Macromolecular interactions (i.e. protein-protein or DNA/RNA-protein interactions) play important cellular roles, including cellular communication and programmed cell death. Small-molecule chemical probes are crucial for dissecting these highly organized interactions, for mapping their function at the molecular level and developing new therapeutics. The lack of ideal chemical probes required to understand macromolecular interactions is the missing link in the next step of dissecting such interactions. Unfortunately, the classical combinatorial-chemistry community has not successfully provided the required probes (i.e. natural product inspired chemical probes that are rich in stereochemical and three-dimensional structural diversity) to achieve these goals. The emerging area of diversity-oriented synthesis (DOS) is beginning to provide natural product-like chemical probes that may be useful in this arena.