Meiying Cui; MIchelle Patino Gaillez; Dzung Nguyen; Stephan Heiden; Weilin Lin; Michael Thompson; Francesco Reddavide; Qinchang Chen; Yixin Zhang
Nat. Commun., 2023, 14, 1481
https://doi.org/10.1038/s41467-023-37071-1

Abstract

The split-and-pool method has been widely used to synthesize chemical libraries of a large size, albeit without the possibility of meaningful quality control. In contrast, a self-assembled DNA-encoded chemical library (DEL) allows us to construct an m x n-member library by mixing an m-member and an n-member pre-purified sub-libraries. Herein, we report a trio-pharmacophore DEL (T-DEL) of m x l x n members through assembling three pre-purified and validated sub-libraries. The middle sub-library is synthesized using DNA-templated synthesis with different reaction mechanisms and designed as a linkage connecting the fragments displayed on the flanking two sub-libraries. In spite of assembling three fragments, the resulting compounds do not exceed the up-to-date standard of molecular weight regarding drug-likeness. The utility of T-DEL has been demonstrated in linker optimization for known binding fragments against trypsin and carbonic anhydrase II and de novo selections against matrix metalloprotease-2 and − 9.