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Breaking the Dogma of the Metal‐Coordinating Carboxylate Group in Integrin Ligands: Introducing Hydroxamic Acids to the MIDAS To Tune Potency and Selectivity
Author(s) -
Heckmann Dominik,
Laufer Burkhardt,
Marinelli Luciana,
Limongelli Vittorio,
Novellino Ettore,
Zahn Grit,
Stragies Roland,
Kessler Horst
Publication year - 2009
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.200900206
Subject(s) - hydroxamic acid , integrin , chemistry , carboxylate , residue (chemistry) , ligand (biochemistry) , stereochemistry , potency , selectivity , group (periodic table) , receptor , metal , combinatorial chemistry , biochemistry , in vitro , organic chemistry , catalysis
A suitable substitute : All integrin receptors bind their ligands, which contain an aspartate residue, in the metal‐ion‐ dependent adhesion site (MIDAS). So far all attempts to replace the carboxyl group of aspartate with other, pharmacologically favorable isosteric groups have failed. Now it has been shown that a hydroxamic acid group can replace the carboxyl group; the resulting ligand retains its high binding activity. The picture shows one such ligand in the binding site of αvβ3.