A 403,200-Compound Peptide-Like DNA-Encoded Library

Summary. Researchers at Uppsala University, KTH Royal Institute of Technology and the Science for Life Laboratory in Sweden reported in ACS Medicinal Chemistry Letters, published online on 12 October, the design and synthesis of a three-cycle, peptide-like DNA-encoded library (DEL) of 403,200 compounds. DNA-encoded libraries can screen very large compound sets in one experiment, but covering lead-like chemical space remains difficult. The team used a chemical-space model built from 4,774 commercially available amino-acid building blocks to find residues that were underrepresented in an earlier design and then added those blocks to broaden physicochemical diversity before split-and-pool synthesis.

Research context (RUO). After synthesis, affinity selections against three purified protein targets were used to check library performance. Selections against carbonic anhydrase II recovered a known sulfonamide-containing pharmacophore, which the authors take as evidence that a medium-sized, computationally guided DEL can still find specific binding motifs. The paper is a library-design and selection methods report; it does not present a clinical programme or a therapeutic recommendation. For laboratories that build or buy peptide-like DELs, it is a concrete example of using an in silico diversity audit to steer which amino-acid building blocks enter a three-cycle synthesis. Yield, purity and full hit lists should be read from the article itself.