Molecular recognition at the active site of catechol-omethyltransferase: Energetically favorable replacement of a water molecule imported by a bisubstrate inhibitor

Abstract

The import business: The binding mode of highly potent bisubstrate inhibitors of catechol-O-methyltransferase (COMT) has been elucidated by X-ray crystal structures of ternary complexes with COMTand a Mg2+ ion (see picture). A single ligand-imported water molecule is replaced, with a gain in binding free enthalpy of at least -1.8 kcal mol-1 compensating the costs of the energetically unfavorable conformation of the ligand in the bound state. © 2009 Wiley-VCH Verlag GmbH & Co. KGaA.