DNA-Encoded Dynamic Chemical Library and Its Applications in Ligand Discovery

Dynamic combinatorial library (DCL)
has emerged as an efficient
tool for ligand discovery and become an important discovery modality
in biomedical research. However, the applications of DCLs have been
significantly hampered by low library diversity and limited analytical
methods capable of processing large libraries. Here, we report a strategy
that has addressed this limitation and can select cooperatively binding
small-molecule pairs from large-scale dynamic libraries. Our approach
is based on DNA-mediated dynamic hybridization, DNA-encoding, and
a photo-cross-linking-based decoding scheme. To demonstrate the generality
and performance of this approach, a 10 000-member DNA-encoded
dynamic library has been prepared and selected against six protein
targets. Specific binders have been identified for each target, and
we have validated the biological activities of selected ligands for
the targets that are implicated in important cellular functions including
protein deacetylation and sumoylation. Notably, a series of novel
and selective sirtuin-3 inhibitors have been developed. Our study
has circumvented a major obstacle in DCL and may provide a broadly
applicable method for ligand discovery against biological targets.