Peixiang Ma; Hongtao Xu; Jie Li; Fengping Lu; Fei Ma; Shuyue Wang; Huan Xiong; Wei Wang; Damiano Buratto; Francesco Zonta; Nan Wang; Kaiwen Liu; Tian Hua; Zhi-Jie Liu; Guang Yang; Richard A. Lerner
Angew. Chem. Int. Ed. Engl., 2019, 58(27), 9254-9261
https://doi.org/10.1002/anie.201901485

Abstract

DNA encoded chemical libraries (DELs) link the powers of genetics and chemical synthesis via combinatorial optimization. Through combinatorial chemistry DELs can grow to the unprecedented size of billions to trillions, providing a rich chemical diversity for biological and pharmaceutical research. While in most cases at the molecular level, the diversity is confined to available building blocks of DNA compatible chemical reactions, modern chemical methods are now being used to increase the diversity. To take full advantage of the DEL approach, linking the power of genetics directly to chemical structures would offer even greater diversity in a finite chemical world. Natural products have evolved an incredible structural diversity along with their biological evolution. Here we use traditional Chinese medicine (TCM) as an example, because there are many of them, they are functionally diverse, and they can be obtained in high purity. We describe a late stage modification toolbox approach to annotate these complex organic compounds with amplifiable DNA barcodes, which could be easily incorporated into a DEL. The method of end‐products labeling also generates a cluster of isomers with a single DNA tag at different sites. These isomers provide an additional spatial diversity for multiple accessible pockets of targeted proteins. Notably, a novel PARP‐1 inhibitor with TCM activity has been identified from the natural products enriched DEL (nDEL).