Dominik K. Kölmel; Hongyao Zhu; Mark E. Flanagan; Sylvie K. Sakata; Anthony R. Harris; Jinqiao Wan; Barry A. Morgan
Chem. Rec., 2021, 21(4), 616-630
https://doi.org/10.1002/tcr.202000148

Abstract

This Personal Account describes the authors' foray into DNA-encoded libraries. The article addresses several key aspects of this hit generation technology, from the development of new synthetic methodology to the subsequent conception, design, and delivery of a DNA-encoded library. In particular, we have been engaged in adapting photocatalytic reactions to the idiosyncratic requirements of DNA-encoded chemistry. We have chosen one such methodology, namely a photocatalytic [2+2] cycloaddition reaction, to showcase how we employed property-based computational analyses to guide the selection and validation of building blocks for the production of a library. Ultimately, these novel bond disconnections and design principles led to the assembly of a DNA-encoded library that is composed of structurally diverse compounds within largely desirable property space and, therefore, well positioned to deliver novel chemical matter for drug discovery programs.