Scanning Protein Surfaces with DNA‐Encoded Libraries
Understanding 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 surf...
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Veröffentlicht in: | ChemMedChem 2021-04, Vol.16 (7), p.1048-1062 |
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Sprache: | eng |
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Zusammenfassung: | Understanding 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.
DELving into the library: Protein surface binders include chemically modified peptides and functional peptidomimetics acting as protein–protein interaction inhibitors and compounds binding to the surface of GPCRs and kinases. Several such compounds have been identified from focused libraries, thus showing the utility of DNA‐encoded chemical libraries (DELs) for improving the potency of weak, say, fragment‐like, starting points. |
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ISSN: | 1860-7179 1860-7187 |
DOI: | 10.1002/cmdc.202000869 |