Molecular Recognition at the Active Site of Catechol-O-methyltransferase (COMT): Adenine Replacements in Bisubstrate Inhibitors (pages 6369–6381)
Dr. Manuel Ellermann, Dr. Ralph Paulini, Dr. Roland Jakob-Roetne, Dr. Christian Lerner, Dr. Edilio Borroni, Doris Roth, Dr. Andreas Ehler, Dr. W. Bernd Schweizer, Dr. Daniel Schlatter, Dr. Markus G. Rudolph and Prof. Dr. François Diederich
Article first published online: 27 APR 2011 | DOI: 10.1002/chem.201003648
Replacements for adenine: The molecular recognition properties of the adenine binding site of catechol-O-methyltransferase (COMT) were investigated. A series of bisubstrate inhibitors with novel substitutes for adenine were synthesized, resulting in IC50 values down to 6 nM. The most important protein–ligand interactions were identified with the help of six high-resolution X-ray cocrystal structures of the inhibitors bound to COMT in the presence of Mg2+. The role of water molecules in adjusting and mediating protein–ligand interactions in the binding pocket is highlighted.