Verena B. K. Kunig; Marco Potowski; Mateja Klika Skopic; Andreas Brunschweiger
ChemMedChem, 2021, 16(7), 1048-1062
https://doi.org/10.1002/cmdc.202000869

Abstract

Understanding the ligandability of a target protein, defined as the capability of a protein to bind drug‐like compounds on any sites, can give important stimuli for drug development projects. For instance, inhibition on protein‐protein interaction usually depends on identification of protein surface binders. DNA‐encoded chemical libraries (DELs) allow for scanning protein surfaces with large chemical space. Encoded library selection screens uncovered several protein‐protein interaction inhibitors and compounds binding to the surface of G protein‐coupled receptors (GPCRs) and kinases. The protein surface‐binding chemotypes from DELs are predominantly chemically modified and cyclized peptides, and functional small molecule peptidomimetics. Peptoid libraries and structural peptidomimetics have been less studied in the DEL field, hinting at hitherto less populated chemical space and suggesting alternative library designs. Roughly a third of the bioactive molecules evolved from smaller, target‐focused libraries. They showcase the potential of encoded libraries to identify more potent molecules from weak, e.g. fragment‐like, starting points.