Kunig, Verena B. K.Potowski, MarcoKlika Škopić, MatejaBrunschweiger, Andreas2022-04-272022-04-272020-12-09http://hdl.handle.net/2003/4088510.17877/DE290R-22742Understanding the ligandability of a target protein, defined as the capability of a protein to bind drug-like compounds on any site, can give important stimuli to drug-development projects. For instance, inhibition of protein–protein interactions usually depends on the identification of protein surface binders. DNA-encoded chemical libraries (DELs) allow scanning of 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 bioactive molecules evolved from smaller, target-focused libraries. They showcase the potential of encoded libraries to identify more potent molecules from weak, for example, fragment-like, starting points.enChemMedChem;16(7)https://creativecommons.org/licenses/by/4.0/DNA-encoded librariesDrug developmentPeptidomimeticsProtein-protein interactionsScreening570540article (journal)