title: Direct comparison of linear and macrocyclic compound libraries as a source of protein ligands.
abstract: There has been much discussion of the potential desirability of macrocyclic molecules for the development of tool compounds and drug leads. But there is little experimental data comparing otherwise equivalent macrocyclic and linear compound libraries as a source of protein ligands. In this Letter, we probe this point in the context of peptoid libraries. Bead-displayed libraries of macrocyclic and linear peptoids containing four variable positions and 0-2 fixed residues, to vary the ring size, were screened against streptavidin and the affinity of every hit for the target was measured. The data show that macrocyclization is advantageous, but only when the ring contains 17 atoms, not 20 or 23 atoms. This technology will be useful for conducting direct comparisons between many different types of chemical libraries to determine their relative utility as a source of protein ligands.
authors.affiliation: Departments of Chemistry and Cancer Biology, The Scripps Research Institute , 130 Scripps Way, Jupiter, Florida 33458, United States.
authors.forename: Yu
authors.initials: Y
authors.lastname: Gao
authors.forename: Thomas
authors.initials: T
authors.lastname: Kodadek
mesh_terms: D008024:Ligands; D047028:Macrocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D019151:Peptide Library; D034444:Peptoids / Q000138:chemical synthesis / Q000737:chemistry*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry*; D019809:Streptavidin / Q000037:antagonists & inhibitors / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D047028:Macrocyclic Compounds; D019151:Peptide Library; D034444:Peptoids; D054852:Small Molecule Libraries; D019809:Streptavidin
keywords: combinatorial library; high-throughput screening; macrocycle; peptoid