Quantitative Validation and Application of the Photo-Cross-Linking Selection for Double-Stranded DNA-Encoded Libraries

The DNA-encoded compound library (DEL) technology has
accelerated
the target hits discovery in new drug development. While affinity-based
DEL selection can distinguish high-affinity ligands, moderate-affinity
ligands are also potential drug candidates with further modifications.
Herein, we designed a photo-cross-linking selection method for DELs
with double-stranded DNA (dsDELs) to screen moderate-affinity ligands.
We constructed two photo-cross-linking libraries with linkers of different
lengths that connect a diazirine group to the DNA encoded compound.
The diazirine group can be activated by UV irradiation and thus bond
with the target protein in a reachable distance. In the model selection,
the feasibility of the photo-cross-linking screening system was verified
by qPCR and NGS technology. Both high-affinity and moderate-affinity
ligands were successfully selected from the libraries.