Toward the assembly and characterization of an encoded library hit confirmation platform: Bead-Assisted Ligand Isolation Mass Spectrometry (BALI-MS) 发布时间：2021-05-11

A B S T R A C T

The ability to predict chemical structure from DNA sequence has to date been a necessary cornerstone of DNAencoded

library technology. DNA-encoded libraries (DELs) are typically screened by immobilized affinity selection

and enriched library members are identified by counting the number of times an individual compound’s

sequence is observed in the resultant dataset. Those with high signal reads (DEL hits) are subsequently followed

up through off-DNA synthesis of the predicted small molecule structures. However, hits followed-up in this

manner often fail to translate to confirmed ligands. To address this low conversion rate of DEL hits to off-DNA

ligands, we have developed an approach that eliminates the reliance on chemical structure prediction from DNA

sequence. Here we describe our method of combining non-combinatorial resynthesis on-DNA following library

procedures as a rapid means to assess the probable molecules attached to the DNA barcode. Furthermore, we

apply our Bead-Assisted Ligand Isolation Mass Spectrometry (BALI-MS) technique to identify the true binders

found within the mixtures of on-DNA synthesis products. Finally, we describe a Normalized Enrichment (NE)

metric that allows for the quantitative assessment of affinity selection in these studies. We exemplify how this

combined approach enables the identification of putative hit matter against a clinically relevant therapeutic

target bisphosphoglycerate mutase, BPGM.

Bioorg. Med. Chem. 41 (2021) 116205

link:https://10.1016/j.bmc.2021.116205