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Impact of a Central Scaffold on the Binding Affinity of Fragment Pairs Isolated from DNA‐Encoded Self‐Assembling Chemical Libraries
Author(s) -
Bigatti Martina,
Dal Corso Alberto,
Vanetti Sara,
Cazzamalli Samuele,
Rieder Ulrike,
Scheuermann Jörg,
Neri Dario,
Sladojevich Filippo
Publication year - 2017
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201700569
Subject(s) - chemistry , dna , nucleic acid , combinatorial chemistry , dissociation constant , fragment (logic) , molecule , drug discovery , fluorescence anisotropy , ligand (biochemistry) , stereochemistry , chemical space , fluorescence , small molecule , computational biology , biochemistry , biology , computer science , receptor , organic chemistry , algorithm , physics , quantum mechanics , membrane
Abstract The screening of encoded self‐assembling chemical libraries allows the identification of fragment pairs that bind to adjacent pockets on target proteins of interest. For practical applications, it is necessary to link these ligand pairs into discrete organic molecules, devoid of any nucleic acid component. Here we describe the discovery of a synergistic binding pair for acid alpha‐1 glycoprotein and a chemical strategy for the identification of optimal linkers, connecting the two fragments. The procedure yielded a set of small organic ligands, the best of which exhibited a dissociation constant of 9.9 n m , as measured in solution by fluorescence polarization.